Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases

ABSTRACT

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-xL proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-xL protein.

This application is a continuation of U.S. patent application Ser. No.13/649,900, filed Oct. 11, 2012, which claims priority to U.S.Provisional Application No. 61/547,162, filed Oct. 14, 2011, which arehereby incorporated by reference in their entireties into thisapplication.

FIELD OF THE INVENTION

This invention pertains to compounds which inhibit the activity ofBcl-xL anti-apoptotic proteins, compositions containing the compounds,and methods of treating diseases during which anti-apoptotic Bcl-xLproteins are expressed.

BACKGROUND OF THE INVENTION

Apoptosis is recognized as an essential biological process for tissuehomeostasis of all living species. In mammals in particular, it has beenshown to regulate early embryonic development. Later in life, cell deathis a default mechanism by which potentially dangerous cells (e.g., cellscarrying cancerous defects) are removed. Several apoptotic pathways havebeen uncovered, and one of the most important involves the Bcl-2 familyof proteins, which are key regulators of the mitochondrial (also called“intrinsic”) pathway of apoptosis. See, Danial, N. N. and Korsmeyer, S.J. Cell (2004) 116, 205-219. The structural homology domains BH1, BH2,BH3 and BH4 are characteristic of this family of proteins. The Bcl-2family of proteins can be further classified into three subfamiliesdepending on how many of the homology domains each protein contains andon its biological activity (i.e., whether it has pro- or anti-apoptoticfunction).

The first subgroup contains proteins having all 4 homology domains,i.e., BH1, BH2, BH3 and BH4. Their general effect is anti-apoptotic,that is to preserve a cell from starting a cell death process. Proteinssuch as, for example, Bcl-2, Bcl-w, Bcl-xL, Mcl-1 and Bfl-1/A1 aremembers of this first subgroup. Proteins belonging to the secondsubgroup contain the three homology domains BH1, BH2 and BH3, and have apro-apoptotic effect. The two main representative proteins of thissecond subgroup are Bax and Bak. Finally, the third subgroup is composedof proteins containing only the BH3 domain and members of this subgroupare usually referred to as “BH3-only proteins.” Their biological effecton the cell is pro-apoptotic. Bim, Bid, Bad, Bik, Noxa, Hrk, Bmf, andPuma are examples of this third subfamily of proteins. The exactmechanism by which the Bcl-2 family proteins regulate cell death isstill not entirely known and understanding this mechanism is an activearea of research in the science community. In one hypothesis ofregulation of cell death by Bcl-2 family proteins, the BH3-only proteinsare further categorized as either “activator” (e.g., Bim and Bid) or“sensitizer” (e.g., Bad, Bik, Noxa, Hrk, Bmf, and Puma) proteinsdepending on their regulatory function.

The key to tissue homeostasis is achieving the delicate balance in theinteractions among the three subgroups of protein in cells. Recentstudies have tried to elucidate the mechanisms by which pro-apoptoticand anti-apoptotic subgroups of Bcl-2 family proteins interact to allowa cell to undergo programmed cell death. After receiving intra- orextracellular signals in cells, post-translational or transcriptionalactivation of BH3-only proteins occurs. The BH3-only proteins are theprimary inducers of an apoptotic cascade that includes, as one step, theactivation of the pro-apoptotic proteins Bax and Bak on themitochondrial membrane in cells. Upon activation of Bax and/or Bak thatare either already anchored to the mitochondrial membrane or migrate tothis membrane, Bax and/or Bak oligomerize to result in mitochondrialouter membrane permeabilization (MOMP), the release of cytochrome C, anddownstream activation of effector caspases, to ultimately result in cellapoptosis. Some researchers hypothesize that certain BH3-only proteins(e.g., Puma, Bim, Bid) are “activators” in that these proteins directlyengage pro-apoptotic proteins Bax and Bak to initiate MOMP, while otherBH3-only proteins (e.g., Bad, Bik and Noxa) are “sensitizers” and induceBax and Bak oligomerization indirectly by binding anti-apoptoticproteins (e.g., Bcl-2, Bcl-xL, Bcl-w, Mcl-1) and displacing and“freeing-up” the “activator” BH3-only proteins, which subsequently bindto and activate pro-apoptotic proteins (e.g., Bax, Bak) to induce celldeath. Other researchers suggest that anti-apoptotic proteins engage andseqeuester Bax and Bak directly and all BH3-only proteins regulates thisinteraction by binding to anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL,Bcl-w, Mcl-1) which results in the release Bax and Bak. See, Adams, J.M. and Cory S. Oncogene (2007) 26, 1324-1337; Willis, S. N. et al.Science (2007) 315, 856-859. Although the exact interactions throughwhich the anti- and pro-apoptotic Bcl-2 family proteins regulateapoptosis remain under debate, there is a large body of scientificevidence to show that compounds which inhibit the binding of BH3-onlyproteins to anti-apoptotic Bcl-2 family proteins promote apoptosis incells.

Dysregulated apoptotic pathways have been implicated in the pathology ofmany significant diseases such as neurodegenerative conditions(up-regulated apoptosis), such as for example, Alzheimer's disease; andproliferative diseases (down-regulated apoptosis) such as for example,cancer, autoimmune diseases and pro-thrombotic conditions.

In one aspect, the implication that down-regulated apoptosis (and moreparticularly the Bcl-2 family of proteins) is involved in the onset ofcancerous malignancy has revealed a novel way of targeting this stillelusive disease. Research has shown, for example, the anti-apoptoticproteins, Bcl-2 and Bcl-xL, are over-expressed in many cancer celltypes. See, Zhang J. Y., Nature Reviews/Drug Discovery, (2002) 1, 101;Kirkin, V. et al. Biochimica et Biophysica Acta (2004) 1644, 229-249;and Amundson, S. A. et al. Cancer Research (2000) 60, 6101-6110. Theeffect of this deregulation is the survival of altered cells which wouldotherwise have undergone apoptosis in normal conditions. The repetitionof these defects associated with unregulated proliferation is thought tobe the starting point of cancerous evolution. Additionally, research hasshown that BH3-only proteins can act as tumor suppressors when expressedin diseased animals.

These findings as well as numerous others have made possible theemergence of new strategies in drug discovery for targeting cancer. If asmall molecule that could mimic the effect of BH3-only proteins wereable to enter the cell and overcome the anti-apoptotic proteinover-expression, then it could be possible to reset the apoptoticprocess. This strategy can have the advantage that it can alleviate theproblem of drug resistance which is usually a consequence of apoptoticderegulation (abnormal survival).

Researchers also have demonstrated that platelets also contain thenecessary apoptotic machinery (e.g., Bax, Bak, Bcl-xL, Bcl-2, cytochromec, caspase-9, caspase-3 and APAF-1) to execute programmed cell deaththrough the intrinsic apoptotic pathway. Although circulating plateletproduction is a normal physiological process, a number of diseases arecaused or exacerbated by excess of, or undesired activation of,platelets. The above suggests that therapeutic agents capable ofinhibiting anti-apoptotic proteins in platelets and reducing the numberof platelets in mammals maybe useful in treating pro-thromboticconditions and diseases that are characterized by an excess of, orundesired activation of, platelets.

We have developed a class of small molecule BH3-only protein mimetics,i.e., ABT-737 and ABT-263, that bind strongly to a subset ofanti-apoptotic Bcl-2 proteins including Bcl-2, Bcl-w and Bcl-xL, butonly weakly to Mcl-1 and A1, and exhibits mechanism-based cytotoxicity.These compounds were tested in animal studies and demonstrated cytotoxicactivity in certain xenograft models as single agents, as well asenhanced the effects of a number of chemotherapeutic agents on otherxenograft models when used in combination. See, Tse, C. et al. CancerRes (2008) 68, 3421-3428; and van Delft, M. F. et al. Cancer Cell (2006)10, 389-399. These in vivo studies suggest the potential utility ofinhibitors of anti-apoptotic Bcl-2 family proteins for the treatment ofdiseases that involve a dysregulated apoptotic pathway.

The natural expression levels of anti-apoptotic Bcl-2 family proteinsmembers vary in different cell types. For example, in young platelets,Bcl-xL protein is highly expressed and plays an important role inregulating cell death (life span) of platelets. Also, in certain cancercell types, the cancer cell's survival is attributed to thedysregulation of the apoptotic pathway caused by the over-expression ofone or more anti-apoptotic Bcl-2 protein family members. In view of theimportant role for Bcl-2 family of proteins in regulating apoptosis inboth cancerous and normal (i.e., non-cancerous) cells, and therecognized inter-cell type variability of Bcl-2 family proteinexpression, it is advantageous to have a small molecule inhibitor thatselectively targets and preferably binds to one type or a subset ofanti-apoptotic Bcl-2 protein(s), for example, to an anti-apoptotic Bcl-2family member that overexpressed in a certain cancer type. Such aselective compound also may confer certain advantages in the clinicalsetting, by providing, for example, the flexibility to select a dosingregimen, a reduced on-target toxic effect in normal cells, among others(e.g., lymphopenia has been observed in Bcl-2 deficient mice). See,Nakayama, K. et al. PNAS (1994) 91, 3700-3704.

In view of the above, there is a need in the art for small moleculestherapeutics that can selectively inhibit the activity of one type or asubset of anti-apoptotic Bcl-2 proteins, for example, of a Bcl-xLanti-apoptotic protein. The present invention fulfills at least thisneed.

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts thereof, which are useful as inhibitorsof anti-apoptotic Bcl-xL proteins, the compounds having Formula (I)

wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

Y¹ is phenylene or C₅₋₆ heteroarylene; optionally fused to one or tworings selected from the group consisting of C₃₋₈ cycloalkane, C₃₋₈cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein Y¹ is optionally substituted with one, two,three, or four substituents independently selected from the groupconsisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵,OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₅, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r);

Y² is C₈₋₁₄ cycloalkyl, C₈₋₁₄ cycloalkenyl, C₈₋₁₄ heterocycloalkyl, orC₈₋₁₄ heterocycloalkenyl; optionally fused to one or two rings selectedfrom the group consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene,benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein Y² is optionally substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸,OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸,NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R¹⁴ and R¹⁴;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, C(O)R¹⁵,CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁵)₂,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶, SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, C(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R¹⁶, NR¹⁶S(O)₂R¹⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR¹⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R¹⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R¹⁶)₂, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH₂, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl;

R¹² and R¹³, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of O—(C₁₋₄alkyl), NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O), OH, CN, NO₂, OCF₃,OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6; and

p is 0, 1, or 2.

In another embodiment of Formula (I), Y¹ is pyrrolyl, pyrazolyl, ortriazolyl.

In another embodiment of Formula (I), Y¹ is pyridinyl or phenyl.

In another embodiment of Formula (I), X is X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (I), Y¹ ispyrrolyl, pyrazolyl, or triazolyl, and X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (I), Y¹ ispyridinyl or phenyl, and X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴.

In another embodiment of Formula (I), Y¹ is pyrrolyl, pyrazolyl, ortriazolyl; and Z¹ is selected from the group consisting of

In another embodiment of Formula (I), Y¹ is pyridinyl or phenyl; and Z¹is selected from the group consisting of

In another embodiment of Formula (I), Y¹ is pyridinyl or phenyl; L¹ is(CR⁶R⁷)_(q); and Y² is selected from the group consisting of C₈₋₁₄cycloalkyl, and C₈₋₁₄ heterocycloalkyl; wherein R⁶ and R⁷, at eachoccurrence, are hydrogen; and q is 1 or 2. In another embodiment ofFormula (I), Y¹ is pyrrolyl, pyrazolyl, or triazolyl; L¹ is (CR⁶R⁷)_(q);and Y² is selected from the group consisting of C₈₋₁₄ cycloalkyl, andC₈₋₁₄ heterocycloalkyl; wherein R⁶ and R⁷, at each occurrence, arehydrogen; and q is 1 or 2.

In another embodiment of Formula (I), Y¹ is pyrrolyl, pyrazolyl, ortriazolyl; L¹ is selected from the group consisting of(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r); Y² is selected from the groupconsisting of C₈₋₁₄ cycloalkyl and C₈₋₁₄ heterocycloalkyl; s is 0; r is0 or 1; R^(6A) is independently selected from the group consisting ofhydrogen, and C₁₋₆ alkyl; and R⁶ and R⁷, at each occurrence, arehydrogen. In another embodiment of Formula (I), Y¹ is pyridinyl orphenyl; L¹ is selected from the group consisting of(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)S—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),and (CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r); Y² is selected from the groupconsisting of C₈₋₁₄ cycloalkyl, and C₈₋₁₄ heterocycloalkyl; s is 0; r is0 or 1; R^(6A) is independently selected from the group consisting ofhydrogen, and C₁₋₆ alkyl; and R⁶ and R⁷, at each occurrence, arehydrogen.

Still another embodiment pertains to a compound having Formula (I),selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3,5-dimethyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(spiro[3.5]non-7-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-hydroxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(2-methoxyethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5,7-trimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-bromotricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(propan-2-yloxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(morpholin-4-yl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{6-[(methylsulfonyl)carbamoyl]-5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{6-[(cyclopropylsulfonyl)carbamoyl]-5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-(2H-tetrazol-5-yl)pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-4-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-{3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl})pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3-[2-(morpholin-4-yl)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-yloxy]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[4,5-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[4,5-c]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(1,1-dioxidothiomorpholin-4-yl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-2-methyl-1-[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)ethyl]-1H-pyrrol-3-yl}pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{5-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{5-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]-6-[(cyclopropylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxy-5,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[(morpholin-4-ylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-[5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-{[(trifluoromethyl)sulfonyl]carbamoyl}pyridin-2-yl]-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{6-[(cyclopropylsulfonyl)carbamoyl]-5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-chloro-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)(1,1-²H₂)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(2-methoxyethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclooctyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylamino]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(imidazo[1,2-a]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfamoyl]phenyl})pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbamoyl]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]amino}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[2-(2-methoxyethyl)tricyclo[3.3.1.1^(3,7)]dec-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-1,2,3-triazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-cyano-3-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfonyl)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-[cyclooctyl(methyl)amino]-3′-methyl-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3-[2-(2-methoxyethoxy)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[(tricyclo[3.3.1.1^(3,7)]dec-2-yl]carbamoyl}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[2-(methylsulfonyl)ethoxy]cyclooctyl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-1,2,3-triazol-4-yl]pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl)amino]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-2-yl]sulfamoyl}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfonyl)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-2-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-2-methyl-1-[(3-methyl-2-oxatricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrrol-3-yl}pyridine-2-carboxylic    acid;-   6-[8-(imidazo[1,2-a]pyrazin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl)-3,4′-bipyridine-2-carboxylic    acid;-   2-{6-[(methylsulfonyl)carbamoyl]-5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-([1,3]thiazolo[5,4-b]pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylamino)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(imidazo[1,2-b]pyridazin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(5-methoxyspiro[2.5]oct-5-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(methylsulfonyl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,5-dimethyl-7-[2-(methylamino)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(2-{2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({8-[(benzyloxy)carbonyl]-8-azabicyclo[3.2.1]oct-3-yl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-6′-oxo-1′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1′,6′-dihydro-3,3′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyl-7-(2-{2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl})-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid; and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.

Another embodiment pertains to a composition for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositioncomprising an excipient and a therapeutically effective amount of acompound of Formula (I).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient therapeutically effective amount of thecompound of Formula (I) and a therapeutically effective amount of oneadditional therapeutic agent or more than one additional therapeuticagent.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

Unless otherwise defined herein, scientific and technical terms used inconnection with the present invention shall have the meanings that arecommonly understood by those of ordinary skill in the art. The meaningand scope of the terms should be clear, however, in the event of anylatent ambiguity, definitions provided herein take precedent over anydictionary or extrinsic definition. In this application, the use of “or”means “and/or” unless stated otherwise. Furthermore, the use of the term“including”, as well as other forms, such as “includes” and “included”,is not limiting. With reference to the use of the words “comprise” or“comprises” or “comprising” in this patent application (including theclaims), Applicants note that unless the context requires otherwise,those words are used on the basis and clear understanding that they areto be interpreted inclusively, rather than exclusively, and thatApplicants intend each of those words to be so interpreted in construingthis patent application, including the claims below. For a variable thatoccurs more than one time in any substituent or in the compound of theinvention or any other formulae herein, its definition on eachoccurrence is independent of its definition at every other occurrence.Combinations of substituents are permissible only if such combinationsresult in stable compounds. Stable compounds are compounds which can beisolated in a useful degree of purity from a reaction mixture.

It is meant to be understood that proper valences are maintained for allcombinations herein, that monovalent moieties having more than one atomare attached through their left ends, and that divalent moieties aredrawn from left to right.

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkyl” (alone or in combination with another term(s)) means astraight- or branched-chain saturated hydrocarbyl substituent typicallycontaining from 1 to about 10 carbon atoms; or in another embodiment,from 1 to about 8 carbon atoms; in another embodiment, from 1 to about 6carbon atoms; and in another embodiment, from 1 to about 4 carbon atoms.Examples of such substituents include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,and hexyl and the like.

The term “alkenyl” (alone or in combination with another term(s)) meansa straight- or branched-chain hydrocarbyl substituent containing one ormore double bonds and typically from 2 to about 10 carbon atoms; or inanother embodiment, from 2 to about 8 carbon atoms; in anotherembodiment, from 2 to about 6 carbon atoms; and in another embodiment,from 2 to about 4 carbon atoms. Examples of such substituents includeethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl,1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl and the like.

The term “alkynyl” (alone or in combination with another term(s)) meansa straight- or branched-chain hydrocarbyl substituent containing one ormore triple bonds and typically from 2 to about 10 carbon atoms; or inanother embodiment, from 2 to about 8 carbon atoms; in anotherembodiment, from 2 to about 6 carbon atoms; and in another embodiment,from 2 to about 4 carbon atoms. Examples of such substituents includeethynyl, 2-propynyl, 3-propynyl, 2-butynyl, and 3-butynyl and the like.

The term “carbocyclyl” (alone or in combination with another term(s))means a saturated cyclic (i.e., “cycloalkyl”), partially saturatedcyclic (i.e., “cycloalkenyl”), or completely unsaturated (i.e., “aryl”)hydrocarbyl substituent containing from 3 to 14 carbon ring atoms (“ringatoms” are the atoms bound together to form the ring or rings of acyclic substituent). A carbocyclyl may be a single-ring (monocyclic) orpolycyclic ring structure.

A carbocyclyl may be a single ring structure, which typically containsfrom 3 to 8 ring atoms, more typically from 3 to 6 ring atoms, and evenmore typically 5 to 6 ring atoms. Examples of such single-ringcarbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl(cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl,cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl,cyclohexadienyl, cyclooxtanyl, and phenyl. A carbocyclyl mayalternatively be polycyclic (i.e., may contain more than one ring).Examples of polycyclic carbocyclyls include bridged, fused, andspirocyclic carbocyclyls. In a spirocyclic carbocyclyl, one atom iscommon to two different rings. Examples of spirocyclic carbocyclylsinclude spiropentanyl, spiro[3.5]nonanyl, and spiro[2.5]octanyl. In abridged carbocyclyl, the rings share at least two common non-adjacentatoms. Examples of bridged carbocyclyls include bicyclo[2.2.1]heptanyl,bicyclo[2.2.1]hept-2-enyl, and adamantanyl(tricyclo[3.3.1.1^(3,7)]decanyl). In a fused-ring carbocyclyl system,two or more rings may be fused together, such that two rings share onecommon bond. Examples of two- or three-fused ring carbocyclyls includenaphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl(dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.

The term “cycloalkyl” (alone or in combination with another term(s))means a saturated cyclic hydrocarbyl substituent containing from 3 to 14carbon ring atoms. A cycloalkyl may be a single carbon ring, whichtypically contains from 3 to 8 carbon ring atoms and more typically from3 to 6 ring atoms. Examples of single-ring cycloalkyls includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, andcyclooctanyl. A cycloalkyl may alternatively be polycyclic or containmore than one ring. Examples of polycyclic cycloalkyls include bridged,fused, and spirocyclic carbocyclyls. Examples of bridged cycloalkylsinclude adamantanyl (tricyclo[3.3.1.1^(3,7)]decanyl), andbicyclo[3.1.1]heptanyl.

The term “C_(x)-C_(y) cycloalkyl” means a cycloalkyl ring systemcontaining from x to y carbon atoms. For example “C₃-C₇ cycloalkyl”means a cycloalkyl ring system containing from 3 to 7 carbon atoms.

The term “cycloalkenyl” (alone or in combination with another term(s))means a partially saturated cyclic hydrocarbyl substituent containingfrom 3 to 14 carbon ring atoms. A cycloalkenyl may be a single carbonring, which typically contains from 3 to 8 carbon ring atoms and moretypically from 4 to 6 ring atoms. Examples of single-ring cycloalkenylsinclude cyclopentenyl, and cyclohexenyl. A cycloalkenyl mayalternatively be polycyclic or contain more than one ring. Examples ofpolycyclic cycloalkenyls include bridged, fused, and spirocycliccarbocyclyls. Examples of bridged cycloalkenyls includebicyclo[2.2.1]hept-2-enyl.

The term “C_(x)-C_(y) cycloalkenyl” means a cycloalkenyl ring systemcontaining from x to y carbon atoms. For example “C₄-C₇ cycloalkenyl”means a cycloalkenyl ring system containing from 4 to 7 carbon atoms.

The term “aryl” (alone or in combination with another term(s)) means anaromatic carbocyclyl containing from 6 to 14 carbon ring atoms. An arylmay be monocyclic or polycyclic (i.e., may contain more than one ring).In the case of polycyclic aromatic rings, only one ring the polycyclicsystem is required to be unsaturated while the remaining ring(s) may besaturated, partially saturated or unsaturated. Examples of aryls includephenyl, naphthalenyl, indenyl, indanyl, and tetrahydronapthyl.

The term “arylene” means a divalent arene.

The term “phenylene” means a divalent benzene.

In some instances, the number of carbon atoms in a substituent (e.g.,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl)is indicated by the prefix “C_(x)-C_(y)-”, wherein x is the minimum andy is the maximum number of carbon atoms. Thus, for example,“C₁-C₆-alkyl” refers to an alkyl containing from 1 to 6 carbon atoms.Illustrating further, “C₃-C₈-cycloalkyl” means a saturated hydrocarbylring containing from 3 to 8 carbon ring atoms.

The term “C_(x-y) branched chain alkyl” means a saturated hydrocarbylsubstituent containing from x to y carbons wherein attachment occursthrough a dialkyl trivalent- or trialkyl tetravalent-carbon radical.Examples of such substituents include isopentanyl (pentan-3-yl),neopentanyl (2,2-dimethylpropan-2-yl), heptan-4-yl, and2,6-dimethylheptan-4-yl.

The term, “C₃₋₁₁ branched chain alkyl” means a saturated hydrocarbylsubstituent containing from 3 to 11 carbons wherein attachment occursthrough a dialkyl trivalent- or trialkyl tetravalent-carbon radical.

The term “hydrogen” (alone or in combination with another term(s)) meansa hydrogen radical, and may be depicted as —H.

The term “hydroxy” (alone or in combination with another term(s)) means—OH.

The term “carboxy” (alone or in combination with another term(s)) means—C(O)—OH.

The term “amino” (alone or in combination with another term(s)) means—NH₂.

The term “halogen” or “halo” (alone or in combination with anotherterm(s)) means a fluorine radical (which may be depicted as —F),chlorine radical (which may be depicted as —Cl), bromine radical (whichmay be depicted as —Br), or iodine radical (which may be depicted as—I).

If a substituent is described as being “substituted”, a non-hydrogenradical is in the place of hydrogen radical on a carbon or nitrogen ofthe substituent. Thus, for example, a substituted alkyl substituent isan alkyl substituent in which at least one non-hydrogen radical is inthe place of a hydrogen radical on the alkyl substituent. To illustrate,monofluoroalkyl is alkyl substituted with a fluoro radical, anddifluoroalkyl is alkyl substituted with two fluoro radicals. It shouldbe recognized that if there are more than one substitution on asubstituent, each non-hydrogen radical may be identical or different(unless otherwise stated).

If a substituent is described as being “optionally substituted”, thesubstituent may be either (1) not substituted or (2) substituted. If asubstituent is described as being optionally substituted with up to aparticular number of non-hydrogen radicals, that substituent may beeither (1) not substituted; or (2) substituted by up to that particularnumber of non-hydrogen radicals or by up to the maximum number ofsubstitutable positions on the substituent, whichever is less. Thus, forexample, if a substituent is described as a heteroaryl optionallysubstituted with up to 3 non-hydrogen radicals, then any heteroaryl withless than 3 substitutable positions would be optionally substituted byup to only as many non-hydrogen radicals as the heteroaryl hassubstitutable positions. To illustrate, tetrazolyl (which has only onesubstitutable position) would be optionally substituted with up to onenon-hydrogen radical. To illustrate further, if an amino nitrogen isdescribed as being optionally substituted with up to 2 non-hydrogenradicals, then a primary amino nitrogen will be optionally substitutedwith up to 2 non-hydrogen radicals, whereas a secondary amino nitrogenwill be optionally substituted with up to only 1 non-hydrogen radical.

This patent application uses the terms “substituent” and “radical”interchangeably.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogenradicals. For example, haloalkyl means an alkyl substituent in which atleast one hydrogen radical is replaced with a halogen radical. Examplesof haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should berecognized that if a substituent is substituted by more than one halogenradical, those halogen radicals may be identical or different (unlessotherwise stated).

The prefix “perhalo” indicates that every hydrogen radical on thesubstituent to which the prefix is attached is replaced withindependently selected halogen radicals, i.e., each hydrogen radical onthe substituent is replaced with a halogen radical. If all the halogenradicals are identical, the prefix typically will identify the halogenradical. Thus, for example, the term “perfluoro” means that everyhydrogen radical on the substituent to which the prefix is attached issubstituted with a fluorine radical. To illustrate, the term“perfluoroalkyl” means an alkyl substituent wherein a fluorine radicalis in the place of each hydrogen radical.

The term “carbonyl” (alone or in combination with another term(s)) means—C(O)—.

The term “aminocarbonyl” (alone or in combination with another term(s))means —C(O)—NH₂.

The term “oxo” (alone or in combination with another term(s)) means(═O).

The term “oxy” (alone or in combination with another term(s)) means anether substituent, and may be depicted as —O—.

The term “hydroxyalkyl” (alone or in combination with another term(s))means -alkyl-OH.

The term “alkylamino” (alone or in combination with another term(s))means -alkyl-NH₂.

The term “alkyloxy” (alone or in combination with another term(s)) meansan alkylether substituent, i.e., —O-alkyl. Examples of such asubstituent include methoxy (—O—CH₃), ethoxy, n-propoxy, isopropoxy,n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

The term “alkylcarbonyl” (alone or in combination with another term(s))means —C(O)-alkyl.

The term “aminoalkylcarbonyl” (alone or in combination with anotherterm(s)) means —C(O)-alkyl-NH₂.

The term “alkyloxycarbonyl” (alone or in combination with anotherterm(s)) means —C(O)—O-alkyl.

The term “carbocyclylcarbonyl” (alone or in combination with anotherterm(s)) means —C(O)-carbocyclyl.

Similarly, the term “heterocyclylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-heterocyclyl.

The term “carbocyclylalkylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-alkyl-carbocyclyl.

Similarly, the term “heterocyclylalkylcarbonyl” (alone or in combinationwith another term(s)) means —C(O)-alkyl-heterocyclyl.

The term “carbocyclyloxycarbonyl” (alone or in combination with anotherterm(s)) means —C(O)—O-carbocyclyl.

The term “carbocyclylalkyloxycarbonyl” (alone or in combination withanother term(s)) means —C(O)—O-alkyl-carbocyclyl.

The term “thio” or “thia” (alone or in combination with another term(s))means replacement by a sulfur radical, i.e. a thiaether substituentmeans an ether substituent wherein a divalent sulfur atom is in theplace of the ether oxygen atom. Such a substituent may be depicted as—S—. For example, “alkyl-thio-alkyl” means alkyl-S-alkyl(alkyl-sulfanyl-alkyl).

The term “thiol” or “sulfhydryl” (alone or in combination with anotherterm(s)) means a sulfhydryl substituent, and may be depicted as —SH.

The term “(thiocarbonyl)” (alone or in combination with another term(s))means a carbonyl wherein the oxygen atom has been replaced with asulfur. Such a substituent may be depicted as —C(S)—.

The term “sulfonyl” (alone or in combination with another term(s)) means—S(O)₂—.

The term “aminosulfonyl” (alone or in combination with another term(s))means —S(O)₂—NH₂.

The term “sulfinyl” or “sulfoxido” (alone or in combination with anotherterm(s)) means —S(O)—.

The term “heterocyclyl” (alone or in combination with another term(s))means a saturated (i.e., “heterocycloalkyl”), partially saturated (i.e.,“heterocycloalkenyl”), or completely unsaturated (i.e., “heteroaryl”)ring structure containing a total of 3 to 14 ring atoms. At least one ofthe ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), withthe remaining ring atoms being independently selected from the groupconsisting of carbon, oxygen, nitrogen, and sulfur. A heterocyclyl maybe a single-ring (monocyclic) or polycyclic ring structure.

A heterocyclyl may be a single ring, which typically contains from 3 to7 ring atoms, more typically from 3 to 6 ring atoms, and even moretypically 5 to 6 ring atoms. Examples of single-ring heterocyclylsinclude furanyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl,thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl,pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl,imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl,tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolyl,thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl,isothiazolidinyl, thiodiazolyl, oxadiazolyl (including1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanyl), or1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl,1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), 1,4-dioxanyl,dioxothiomorpholinyl, oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl,dihydropyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridinyl (azinyl),piperidinyl, diazinyl (including pyridazinyl (1,2-diazinyl), pyrimidinyl(1,3-diazinyl), or pyrazinyl (1,4-diazinyl)), piperazinyl, triazinyl(including 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,2,3-triazinyl)),oxazinyl (including 1,2-oxazinyl, 1,3-oxazinyl, or 1,4-oxazinyl)),oxathiazinyl (including 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl,1,2,5-oxathiazinyl, or 1,2,6-oxathiazinyl)), oxadiazinyl (including1,2,3-oxadiazinyl, 1,2,4-oxadiazinyl, 1,4,2-oxadiazinyl, or1,3,5-oxadiazinyl)), morpholinyl, azepinyl, oxepinyl, thiepinyl,diazepinyl, pyridonyl (including pyrid-2(1H)-onyl and pyrid-4(1H)-onyl),furan-2(5H)-onyl, pyrimidonyl (including pyramid-2(1H)-onyl andpyramid-4(3H)-onyl), oxazol-2(3H)-onyl, 1H-imidazol-2(3H)-onyl,pyridazin-3(2H)-onyl, and pyrazin-2(1H)-onyl.

A heterocyclyl may alternatively be polycyclic (i.e., may contain morethan one ring). Examples of polycyclic heterocyclyls include bridged,fused, and spirocyclic heterocyclyls. In a spirocyclic heterocyclyl, oneatom is common to two different rings. In a bridged heterocyclyl, therings share at least two common non-adjacent atoms. Examples of bridgedheterocyclyls include 2-oxatricyclo[3.3.1.1^(3,7)]decane. In afused-ring heterocyclyl, two or more rings may be fused together, suchthat two rings share one common bond. Examples of fused ringheterocyclyls containing two or three rings include imidazopyrazinyl(including imidazo[1,2-a]pyrazinyl), imidazopyridinyl (includingimidazo[1,2-a]pyridinyl), imidazopyridazinyl (includingimidazo[1,2-b]pyridazinyl), thiazolopyridinyl (includingthiazolo[5,4-c]pyridinyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-b]pyridinyl, and thiazolo[4,5-c]pyridinyl), indolizinyl,pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl,pyridopyridinyl (including pyrido[3,4-b]-pyridinyl,pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl.Other examples of fused-ring heterocyclyls include benzo-fusedheterocyclyls, such as dihydrochromenyl, tetrahydroisoquinolinyl,indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indoleninyl(pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (includingquinolinyl (1-benzazinyl) or isoquinolinyl (2-benzazinyl)),phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (includingcinnolinyl (1,2-benzodiazinyl) or quinazolinyl (1,3-benzodiazinyl)),benzopyranyl (including chromanyl or isochromanyl), benzoxazinyl(including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl,or 3,1,4-benzoxazinyl), benzo[d]thiazolyl, and benzisoxazinyl (including1,2-benzisoxazinyl or 1,4-benzisoxazinyl).

The term “heterocycloalkyl” (alone or in combination with anotherterm(s)) means a saturated heterocyclyl.

The term “C_(x)-C_(y) heterocycloalkyl” means a heterocycloalkyl ringsystem containing from x to y ring atoms. For example “C₃-C₇heterocycloalkyl” means a heterocycloalkyl ring system containing 3 to 7ring atoms.

The term “heterocycloalkenyl” (alone or in combination with anotherterm(s)) means a partially saturated heterocyclyl.

The term “C_(x)-C_(y) heterocycloalkenyl” means a heterocycloalkenylring system containing from x to y ring atoms. For example “C₃-C₇heterocycloalkenyl” means a heterocycloalkenyl ring system containingfrom 3 to 7 ring atoms.

The term “heteroaryl” (alone or in combination with another term(s))means an aromatic heterocyclyl containing from 5 to 14 ring atoms. Aheteroaryl may be a single ring or 2 or 3 fused rings. Examples ofheteroaryls include 6-membered ring substituents such as pyridyl,pyrazyl, pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4- or1,2,3-triazinyl; 5-membered ring substituents such as triazolyl,pyrrolyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl andisothiazolyl; 6/5-membered fused ring substituents such asimidazopyrazinyl (including imidazo[1,2-a]pyrazinyl)imidazopyridinyl(including imidazo[1,2-a]pyridinyl), imidazopyridazinyl (includingimidazo[1,2-b]pyridazinyl), thiazolopyridinyl (includingthiazolo[5,4-c]pyridinyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-b]pyridinyl, and thiazolo[4,5-c]pyridinyl),benzo[d]thiazolyl, benzothiofuranyl, benzisoxazolyl, benzoxazolyl,purinyl, and anthranilyl; and 6/6-membered fused rings such asbenzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, andbenzoxazinyl. Heteroaryls may also be heterocycles having aromatic (4N+2pi electron) resonance contributors such as pyridonyl (includingpyrid-2(1H)-onyl and pyrid-4(1H)-onyl), pyrimidonyl (includingpyramid-2(1H)-onyl and pyramid-4(3H)-onyl), pyridazin-3(2H)-onyl andpyrazin-2(1H)-onyl.

The term “C_(x)-C_(y) heteroaryl” means a heteroaryl ring systemcontaining from x to y ring atoms. For example “C₅-C₆ heteroaryl” meansa heteroaryl ring system containing from 5 to 6 ring atoms.

The term “heteroarylene” means a divalent heteroarene.

A prefix attached to a multi-component substituent only applies to thefirst component. To illustrate, the term “alkylcycloalkyl” contains twocomponents: alkyl and cycloalkyl. Thus, the C₁-C₆— prefix onC₁-C₆-alkylcycloalkyl means that the alkyl component of thealkylcycloalkyl contains from 1 to 6 carbon atoms; the C₁-C₆-prefix doesnot describe the cycloalkyl component. To illustrate further, the prefix“halo” on haloalkyloxyalkyl indicates that only the alkyloxy componentof the alkyloxyalkyl substituent is substituted with one or more halogenradicals. If halogen substitution may alternatively or additionallyoccur on the alkyl component, the substituent would instead be describedas “halogen-substituted alkyloxyalkyl” rather than “haloalkyloxyalkyl.”And finally, if the halogen substitution may only occur on the alkylcomponent, the substituent would instead be described as“alkyloxyhaloalkyl.”

The terms “treat”, “treating” and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms.

The terms “prevent”, “preventing” and “prevention” refer to a method ofpreventing the onset of a disease and/or its attendant symptoms orbarring a subject from acquiring a disease. As used herein, “prevent”,“preventing” and “prevention” also include delaying the onset of adisease and/or its attendant symptoms and reducing a subject's risk ofacquiring a disease.

The term “therapeutically effective amount” refers to that amount of thecompound being administered sufficient to prevent development of oralleviate to some extent one or more of the symptoms of the condition ordisorder being treated.

The term “modulate” refers to the ability of a compound to increase ordecrease the function, or activity, of a kinase. “Modulation”, as usedherein in its various forms, is intended to encompass antagonism,agonism, partial antagonism and/or partial agonism of the activityassociated with kinase. Kinase inhibitors are compounds that, e.g., bindto, partially or totally block stimulation, decrease, prevent, delayactivation, inactivate, desensitize, or down regulate signaltransduction. Kinase activators are compounds that, e.g., bind to,stimulate, increase, open, activate, facilitate, enhance activation,sensitize or up regulate signal transduction.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The “subject” is defined herein to include animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

The term “NH protecting group,” as used herein, meanstrichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl,dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl,acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl,para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl,diphenylmethoxycarbonyl, 1,1-dimethylpropoxy-carbonyl,isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl,1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl,triphenylmethyl, 2-nitrophenylthio, methanesulfonyl,para-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene,2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene,2-hydroxy-1-naphthyl-methylene, 3-hydroxy-4-pyridylmethylene,cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene,3,3-dimethyl-5-oxycyclo-hexylidene, diphenylphosphoryl,dibenzylphosphoryl, 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl,trimethylsilyl, triethylsilyl, and triphenylsilyl.

The term “C(O)OH protecting group,” as used herein, means methyl, ethyl,n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl,naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl,para-methoxybenzyl, bis(para-methoxyphenyl)methyl, acetylmethyl,benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl,para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl2-tetrahydrofuranyl, 2,2,2-trichloro-ethyl, 2-(trimethylsilyl)ethyl,acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl,succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl,1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl,triethylsilyl, triisopropylsilyl, diethylisopropylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl,and tert-butylmethoxyphenylsilyl.

The term “OH or SH protecting group,” as used herein, meansbenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl,diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl,2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl,2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl,allyl, benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl,diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl,2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl,para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl,diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

Compounds

Geometric isomers may exist in the present compounds. Compounds of thisinvention may contain carbon-carbon double bonds or carbon-nitrogendouble bonds in the E or Z configuration, wherein the term “E”represents higher order substituents on opposite sides of thecarbon-carbon or carbon-nitrogen double bond and the term “Z” representshigher order substituents on the same side of the carbon-carbon orcarbon-nitrogen double bond as determined by the Cahn-Ingold-PrelogPriority Rules. The compounds of this invention may also exist as amixture of “E” and “Z” isomers. Substituents around a cycloalkyl orheterocycloalkyl are sometimes designated as being of cis or transconfiguration.

Compounds of this invention may contain asymmetrically substitutedcarbon atoms in the R or S configuration, in which the terms “R” and “S”are as defined by the IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10.Compounds having asymmetrically substituted carbon atoms with equalamounts of R and S configurations are racemic at those carbon atoms.Atoms with an excess of one configuration over the other are assignedthe configuration present in the higher amount, preferably an excess ofabout 85%-90%, more preferably an excess of about 95%-99%, and stillmore preferably an excess greater than about 99%. Accordingly, thisinvention includes racemic mixtures, relative and absolutestereoisomers, and mixtures of relative and absolute stereoisomers.

Isotope Enriched or Labeled Compounds

Compounds of the invention can exist in isotope-labeled or -enrichedform containing one or more atoms having an atomic mass or mass numberdifferent from the atomic mass or mass number most abundantly found innature. Isotopes can be radioactive or non-radioactive isotopes.Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur,fluorine, chlorine, and iodine include, but are not limited to, ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Compounds thatcontain other isotopes of these and/or other atoms are within the scopeof this invention.

In another embodiment, the isotope-labeled compounds contain deuterium(²H), tritium (³H) or ¹⁴C isotopes. Isotope-labeled compounds of thisinvention can be prepared by the general methods well known to personshaving ordinary skill in the art. Such isotope-labeled compounds can beconveniently prepared by carrying out the procedures disclosed in theExamples disclosed herein and Schemes by substituting a readilyavailable isotope-labeled reagent for a non-labeled reagent. In someinstances, compounds may be treated with isotope-labeled reagents toexchange a normal atom with its isotope, for example, hydrogen fordeuterium can be exchanged by the action of a deuteric acid such asD₂SO₄/D₂O. In addition to the above, relevant procedures andintermediates are disclosed, for instance, in Lizondo, J et al., DrugsFut, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3), 673(1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCTpublications WO1997010223, WO2005099353, WO1995007271, WO2006008754;U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421;7,514,068; 7,511,013; and US Patent Application Publication Nos.20090137457; 20090131485; 20090131363; 20090118238; 20090111840;20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and20090082471, the methods are hereby incorporated by reference.

The isotope-labeled compounds of the invention may be used as standardsto determine the effectiveness of Bcl-xL inhibitors in binding assays.Isotope containing compounds have been used in pharmaceutical researchto investigate the in vivo metabolic fate of the compounds by evaluationof the mechanism of action and metabolic pathway of thenonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3,367-391 (1975)). Such metabolic studies are important in the design ofsafe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal., Advances in Drug Research Vol. 14, pp. 2-36, Academic press,London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut.,36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77,79-88 (1999).

In addition, non-radio active isotope containing drugs, such asdeuterated drugs called “heavy drugs,” can be used for the treatment ofdiseases and conditions related to Bcl-xL activity. Increasing theamount of an isotope present in a compound above its natural abundanceis called enrichment. Examples of the amount of enrichment include fromabout 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37,42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol%. Replacement of up to about 15% of normal atom with a heavy isotopehas been effected and maintained for a period of days to weeks inmammals, including rodents and dogs, with minimal observed adverseeffects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770;Thomson J F, Ann. New York Acad. Sci. 1960 84: 736; Czakja D M et al.,Am. J. Physiol. 1961 201: 357). Acute replacement of as high as 15%-23%in human fluids with deuterium was found not to cause toxicity(Blagojevic N et al. in “Dosimetry & Treatment Planning for NeutronCapture Therapy”, Zamenhof R, Solares G and Harling O Eds. 1994.Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab.23: 251 (1997)).

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction. While some of the physical properties of astable isotope-labeled molecule are different from those of theunlabeled one, the chemical and biological properties are the same, withone important exception: because of the increased mass of the heavyisotope, any bond involving the heavy isotope and another atom will bestronger than the same bond between the light isotope and that atom.Accordingly, the incorporation of an isotope at a site of metabolism orenzymatic transformation will slow said reactions potentially alteringthe pharmacokinetic profile or efficacy relative to the non-isotopiccompound.

Suitable groups for X, Y¹, L¹, Y², Z¹, R¹, R², R³, m, n, and p incompounds of Formula (I) are independently selected. The describedembodiments of the present invention may be combined. Such combinationis contemplated and within the scope of the present invention. Forexample, it is contemplated that embodiments for any of X, Y¹, L¹, Y²,Z¹, R¹, R², R³, m, n, and p can be combined with embodiments defined forany other of X, Y¹, L¹, Y², Z¹, R¹, R², R³, m, n, and p.

One embodiment of this invention, therefore, pertains to compounds andtherapeutically acceptable salts, metabolites, prodrugs, salts ofmetabolites, and salts of prodrugs thereof, which are useful asinhibitors of anti-apoptotic Bcl-xL proteins, the compounds havingFormula (I)

wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

Y¹ is phenylene or C₅₋₆ heteroarylene; optionally fused to one or tworings selected from the group consisting of C₃₋₈ cycloalkane, C₃₋₈cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein Y¹ is optionally substituted with one, two,three, or four substituents independently selected from the groupconsisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵,OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₅, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r);

Y² is C₈₋₁₄ cycloalkyl, C₈₋₁₄ cycloalkenyl, C₈₋₁₄ heterocycloalkyl, orC₈₋₁₄ heterocycloalkenyl; optionally fused to one or two rings selectedfrom the group consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene,benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein Y² is optionally substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸,OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸,NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R¹⁴ and R¹⁴;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, C(O)R¹⁵,CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁵)₂,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶, SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, C(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R¹⁶, NR¹⁶S(O)₂R¹⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR¹⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R¹⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R¹⁶)₂, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH₂, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl;

R¹² and R¹³, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of O—(C₁₋₄alkyl), NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O), OH, CN, NO₂, OCF₃,OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6; and

p is 0, 1, or 2.

In one embodiment of Formula (I), m is 0, 1, 2, or 3; n is 0, 1, 2, 3,4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (I), nis 0, 1, or 2. In another embodiment of Formula (I), n is 0, 1, or 2;and each R² is independently deuterium or C₁₋₆ alkyl. In anotherembodiment of Formula (I), m, n, and p are 0.

In one embodiment of Formula (I), X is heteroaryl, which is optionallysubstituted with one, two, three or four R⁴. In another embodiment ofFormula (I), X is heteroaryl, which is unsubstituted. In anotherembodiment of Formula (I), X is heteroaryl, which is substituted withone R⁴. In another embodiment of Formula (I), X is heteroaryl, which issubstituted with two R⁴. In another embodiment of Formula (I), X isheteroaryl, which is substituted with one R⁴, and R⁴ is OR¹² or halogen.In another embodiment of Formula (I), X is heteroaryl, which issubstituted with two R⁴, and each R⁴ is independently OR¹² or halogen.In another embodiment of Formula (I), X is heteroaryl, which issubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (I), X is heteroaryl, which is substituted withtwo R⁴, and each R⁴ is independently F.

In one embodiment of Formula (I), X benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (I), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are unsubstituted. In anotherembodiment of Formula (I), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴. In anotherembodiment of Formula (I), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴. In anotherembodiment of Formula (I), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴, and R⁴ isOR¹² or halogen. In another embodiment of Formula (I), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently OR¹² or halogen. In another embodiment of Formula(I), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which aresubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (I), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently F.

In one embodiment of Formula (I), X is benzo[d]thiazolyl, which isoptionally substituted with one, two, three or four R⁴. In anotherembodiment of Formula (I), X is benzo[d]thiazolyl, which isunsubstituted. In another embodiment of Formula (I), X isbenzo[d]thiazolyl, which is substituted with one R⁴. In anotherembodiment of Formula (I), X is benzo[d]thiazolyl, which is substitutedwith two R⁴. In another embodiment of Formula (I), X isbenzo[d]thiazolyl, which is substituted with one R⁴, and R⁴ is OR¹² orhalogen. In another embodiment of Formula (I), X is benzo[d]thiazolyl,which is substituted with two R⁴, and each R⁴ is independently OR¹² orhalogen. In another embodiment of Formula (I), X is benzo[d]thiazolyl,which is substituted with one R⁴, and R⁴ is Cl, F, or methoxy. Inanother embodiment of Formula (I), X is benzo[d]thiazolyl, which issubstituted with two R⁴, and each R⁴ is independently F.

In one embodiment of Formula (I), Z¹ is selected from the groupconsisting of C(O)OR⁹, C(O)NR¹⁰R¹¹, C(O)R¹¹, NR¹⁰C(O)R¹¹,NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹, C(═NOR¹⁰)NR¹⁰R¹¹,NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹, S(O)₂NR¹⁰R¹¹,N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹, C(═NR¹⁰)NR¹⁰R¹¹,halogen, NO₂, and CN; or Z¹ is selected from the group consisting of

In another embodiment of Formula (I), Z¹ is

In another embodiment of Formula (I), Z¹ is

In another embodiment of Formula (I), Z¹ is

In another embodiment of Formula (I), Z¹ is

In one embodiment of Formula (I), Y¹ is phenylene or C₅₋₆ heteroarylene;optionally fused to one or two rings selected from the group consistingof C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈heterocycloalkane, and C₃₋₈ heterocycloalkene; wherein Y¹ is optionallysubstituted with one, two, three, or four substituents independentlyselected from the group consisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵,C(O)R⁵, CO(O)R⁵, OC(O)R⁵, OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵,NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵, NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂,NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵, NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵,C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵, C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂,SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H, OH, CN, N₅, NO₂, F, Cl, Br and I. Inanother embodiment of Formula (I), Y¹ is phenylene or C₅₋₆heteroarylene; wherein the phenylene and C₅₋₆ heteroarylene representedby Y¹ are optionally substituted with one or two substituentsindependently selected from the group consisting of R⁵, CN, F, Cl, Brand I. In another embodiment of Formula (I), Y¹ is phenylene or C₅₋₆heteroarylene; wherein the phenylene and C₅₋₆ heteroarylene representedby Y¹ are optionally substituted with one or two substituentsindependently selected from the group consisting of R⁵, CN, F, Cl, Brand I; wherein R⁵ is C₁₋₆ alkyl.

In another embodiment of Formula (I), Y¹ is pyrrolyl, pyrazolyl,triazolyl, pyridinyl, or phenyl. In another embodiment of Formula (I),Y¹ is pyrrolyl, pyrazolyl, or triazolyl. In another embodiment ofFormula (I), Y¹ is pyridinyl or phenyl. In another embodiment of Formula(I), Y¹ is pyrrolyl, pyrazolyl, triazolyl, pyridinyl, or phenyl; whereinthe pyrrolyl, pyrazolyl, triazolyl, pyridinyl, and phenyl represented byY¹ are optionally substituted with one or two substituents independentlyselected from the group consisting of R⁵, CN, F, Cl, Br and I. Inanother embodiment of Formula (I), Y¹ is pyrrolyl, pyrazolyl, triazolyl,pyridinyl, or phenyl; wherein the pyrrolyl, pyrazolyl, triazolyl,pyridinyl, and phenyl represented by Y¹ are optionally substituted withone or two substituents independently selected from the group consistingof R⁵, CN, F, Cl, Br and I; wherein R⁵ is C₁₋₆ alkyl.

In one embodiment of Formula (I), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is C₈₋₁₄ cycloalkyl, C₈₋₁₄cycloalkenyl, C₈₋₁₄ heterocycloalkyl, or C₈₋₁₄ heterocycloalkenyl;optionally fused to one or two rings selected from the group consistingof C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈heterocycloalkane, and C₃₋₈ heterocycloalkene; wherein Y² is optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I.

In another embodiment of Formula (I), L¹ is (CR⁶R⁷)_(q); and Y² isselected from the group consisting of C₈₋₁₄ cycloalkyl and C₈₋₁₄heterocycloalkyl; wherein R⁶ and R⁷, at each occurrence, are hydrogen;and q is 1 or 2. In another embodiment of Formula (I), L¹ is selectedfrom the group consisting of (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)C(O)NR^(6A)(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r); Y² is selected from the groupconsisting of C₈₋₁₄ cycloalkyl, and C₈₋₁₄ heterocycloalkyl; s is 0; r is0 or 1; R^(6A) is independently selected from the group consisting ofhydrogen, and C₁₋₆ alkyl; and R⁶ and R⁷, at each occurrence, arehydrogen.

In another embodiment of Formula (I),

X is heteroaryl;

Y is phenylene or C₅₋₆ heteroarylene; wherein Y¹ is optionallysubstituted with one, or two substituents independently selected fromthe group consisting of R⁵, CN, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),and (CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r);

Y² is C₈₋₁₄ cycloalkyl, or C₈₋₁₄ heterocycloalkyl; wherein Y² isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of R⁸, OR⁸, SO₂R⁸,CO(O)R⁸, OH, F, Cl, Br and I;

Z¹ is selected from the group consisting of

R², at each occurrence, is independently C₁₋₆ alkyl;

R⁵, at each occurrence, is independently C₁₋₆ alkyl;

R^(6A) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl;

R⁶ and R⁷, at each occurrence, are each independently hydrogen;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl and heterocyclyl; wherein the R⁸C₁₋₆ alkyl isoptionally substituted with one substituent independently selected fromthe group consisting of R¹⁶, OR¹⁶, SO₂R¹⁶, and NHR¹⁶;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇ cycloalkyl andC₁₋₆ haloalkyl;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, aryl, and heterocycloalkyl; wherein theR¹⁶C₁₋₄ alkyl is optionally substituted with one substituentindependently selected from the group consisting of OCH₃, OCH₂CH₂OCH₃,and OCH₂CH₂NHCH₃;

q is 1 or 2;

s is 0;

r is 0 or 1;

wherein the sum of s and r is 0 or 1;

m is 0;

n is 0, 1, or 2; and

p is 0.

Still another embodiment pertains to a compound having Formula (I)selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl})pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3,5-dimethyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(spiro[3.5]non-7-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-hydroxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(2-methoxyethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5,7-trimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-bromotricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(propan-2-yloxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(morpholin-4-yl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{6-[(methylsulfonyl)carbamoyl]-5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{6-[(cyclopropylsulfonyl)carbamoyl]-5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-(2H-tetrazol-5-yl)pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-4-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3-[2-(morpholin-4-yl)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-yloxy]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[4,5-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[4,5-c]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(1,1-dioxidothiomorpholin-4-yl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-2-methyl-1-[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)ethyl]-1H-pyrrol-3-yl}pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{5-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{5-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]-6-[(cyclopropylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxy-5,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[(morpholin-4-ylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-[5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-{[(trifluoromethyl)sulfonyl]carbamoyl}pyridin-2-yl]-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{6-[(cyclopropylsulfonyl)carbamoyl]-5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-chloro-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)(1,1-²H₂)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(2-methoxyethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[-(2-methoxyethyl)cyclooctyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylamino]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(imidazo[1,2-a]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfamoyl]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbamoyl]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]amino}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[2-(2-methoxyethyl)tricyclo[3.3.1.1^(3,7)]dec-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-1,2,3-triazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-cyano-3-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfonyl)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-[cyclooctyl(methyl)amino]-3′-methyl-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3-[2-(2-methoxyethoxy)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[(tricyclo[3.3.1.1^(3,7)]dec-2-yl]carbamoyl}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[2-(methylsulfonyl)ethoxy]cyclooctyl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-1,2,3-triazol-4-yl]pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl)amino]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-2-yl]sulfamoyl}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfonyl)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-2-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-2-methyl-1-[(3-methyl-2-oxatricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrrol-3-yl}pyridine-2-carboxylic    acid;-   6-[8-(imidazo[1,2-a]pyrazin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl)-3,4′-bipyridine-2-carboxylic    acid;-   2-{6-[(methylsulfonyl)carbamoyl]-5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-([1,3]thiazolo[5,4-b]pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylamino)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(imidazo[1,2-b]pyridazin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(5-methoxyspiro[2.5]oct-5-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(methylsulfonyl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,5-dimethyl-7-[2-(methylamino)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(2-{2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({8-[(benzyloxy)carbonyl]-8-azabicyclo[3.2.1]oct-3-yl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-6′-oxo-1′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1′,6′-dihydro-3,3′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyl-7-(2-{2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl})-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid; and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides compounds of Formula(II)

and therapeutically acceptable salts, metabolites, prodrugs, salts ofmetabolites, and salts of prodrugs thereof, wherein X, L¹, Y², Z¹, R¹,R², R³, m, n, and p are as described herein for Formula (I); R^(x) is asdescribed herein for substituents on Y¹, and o is 0, 1, 2, or 3.

One embodiment of this invention pertains to compounds, andtherapeutically acceptable salts thereof, which are useful as inhibitorsof anti-apoptotic Bcl-xL proteins, the compounds having Formula (II)

wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵,OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₅, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r);

Y² is C₈₋₁₄ cycloalkyl, C₈₋₁₄ cycloalkenyl, C₈₋₁₄ heterocycloalkyl, orC₈₋₁₄ heterocycloalkenyl; optionally fused to one or two rings selectedfrom the group consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene,benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein Y² is optionally substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸,OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸,NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R¹⁴ and R¹⁴;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, C(O)R¹⁵,CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁵)₂,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶, SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, C(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R¹⁶, NR¹⁶S(O)₂R¹⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR¹⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R¹⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R¹⁶)₂, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH₂, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl;

R¹² and R¹³, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of O—(C₁₋₄alkyl), NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O), OH, CN, NO₂, OCF₃,OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6;

o is 0, 1, 2, or 3; and

p is 0, 1, or 2.

In one embodiment of Formula (II), m is 0, 1, 2, or 3; n is 0, 1, 2, 3,4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (II),n is 0, 1, or 2. In another embodiment of Formula (II), n is 0, 1, or 2;and each R² is independently deuterium or C₁₋₆ alkyl. In anotherembodiment of Formula (II), m, n, and p are 0.

In one embodiment of Formula (II), X is heteroaryl, which is optionallysubstituted with one, two, three or four R⁴. In another embodiment ofFormula (II), X is heteroaryl, which is unsubstituted. In anotherembodiment of Formula (II), X is heteroaryl, which is substituted withone R⁴. In another embodiment of Formula (II), X is heteroaryl, which issubstituted with two R⁴. In another embodiment of Formula (II), X isheteroaryl, which is substituted with one R⁴, and R⁴ is OR¹² or halogen.In another embodiment of Formula (II), X is heteroaryl, which issubstituted with two R⁴, and each R⁴ is independently OR¹² or halogen.In another embodiment of Formula (II), X is heteroaryl, which issubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (II), X is heteroaryl, which is substituted withtwo R⁴, and each R⁴ is independently F.

In one embodiment of Formula (II), X benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (II), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are unsubstituted. In anotherembodiment of Formula (II), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴. In anotherembodiment of Formula (II), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴. In anotherembodiment of Formula (II), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴, and R⁴ isOR¹² or halogen. In another embodiment of Formula (II), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently OR¹² or halogen. In another embodiment of Formula(II), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which aresubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (II), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently F.

In one embodiment of Formula (II), X is benzo[d]thiazolyl, which isoptionally substituted with one, two, three or four R⁴. In anotherembodiment of Formula (II), X is benzo[d]thiazolyl, which isunsubstituted. In another embodiment of Formula (II), X isbenzo[dc]thiazolyl, which is substituted with one R⁴. In anotherembodiment of Formula (II), X is benzo[d]thiazolyl, which is substitutedwith two R⁴. In another embodiment of Formula (II), X isbenzo[d]thiazolyl, which is substituted with one R⁴, and R⁴ is OR¹² orhalogen. In another embodiment of Formula (II), X is benzo[d]thiazolyl,which is substituted with two R⁴, and each R⁴ is independently OR¹² orhalogen. In another embodiment of Formula (II), X is benzo[d]thiazolyl,which is substituted with one R⁴, and R⁴ is Cl, F, or methoxy. Inanother embodiment of Formula (II), X is benzo[d]thiazolyl, which issubstituted with two R⁴, and each R⁴ is independently F.

In one embodiment of Formula (II), Z¹ is selected from the groupconsisting of C(O)OR⁹, C(O)NR¹⁰R¹¹, C(O)R¹¹, NR¹⁰C(O)R¹¹,NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹, C(═NOR¹⁰)NR¹⁰R¹¹,NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹, S(O)₂NR¹⁰R¹¹,N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹, C(═NR¹⁰)NR¹⁰R¹¹,halogen, NO₂, and CN; or Z¹ is selected from the group consisting of

In another embodiment of Formula (II), Z¹ is

In another embodiment of Formula (II), Z¹ is

In another embodiment of Formula (II), Z¹ is

In another embodiment of Formula (II), Z¹ is

In one embodiment of Formula (II), o is 0. In another embodiment ofFormula (II), o is 0, 1, 2, or 3. In another embodiment of Formula (II),o is 1, 2, or 3; and R^(x), at each occurrence, is independentlyselected from the group consisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵,C(O)R⁵, CO(O)R⁵, OC(O)R⁵, OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵,NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵, NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂,NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵, NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵,C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵, C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂,SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H, OH, CN, N₅, NO₂, F, Cl, Br and I. Inanother embodiment of Formula (II), o is 1, 2, or 3; and R^(x), at eachoccurrence, is independently selected from the group consisting of R⁵,CN, F, Cl, Br and I. In another embodiment of Formula (II), o is 1, 2,or 3; and R^(x), at each occurrence, is independently selected from thegroup consisting of R⁵, CN, F, Cl, Br and I; wherein R⁵ is C₁₋₆ alkyl.In another embodiment of Formula (II), o is 1 or 2; R^(x) is R⁵ or CN;and R⁵ is CH₃. In another embodiment of Formula (II), o is 1; and R^(x)is CN. In another embodiment of Formula (II), o is 1; and R^(x) is Cl.In another embodiment of Formula (II), o is 1; R^(x) is R⁵; and R⁵ isCH₃.

In one embodiment of Formula (II), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is C₈₋₁₄ cycloalkyl, C₈₋₁₄cycloalkenyl, C₈₋₁₄ heterocycloalkyl, or C₈₋₁₄ heterocycloalkenyl;optionally fused to one or two rings selected from the group consistingof C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈heterocycloalkane, and C₃₋₈ heterocycloalkene; wherein Y² is optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I.

In another embodiment of Formula (II), L¹ is (CR⁶R⁷)_(q); and Y² isselected from the group consisting of C₈₋₁₄ cycloalkyl, and C₈₋₁₄heterocycloalkyl; wherein R⁶ and R⁷, at each occurrence, are hydrogen;and q is 1 or 2. In another embodiment of Formula (II), L¹ is selectedfrom the group consisting of (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r); Y² is selected from the groupconsisting of C₈₋₁₄ cycloalkyl, and C₈₋₁₄ heterocycloalkyl; s is 0; r is0 or 1; R^(6A) is independently selected from the group consisting ofhydrogen, and C₁₋₆ alkyl; and R⁶ and R⁷, at each occurrence, arehydrogen.

In another embodiment of Formula (II),

X is heteroaryl;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, CN, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r);

Y² is C₈₋₁₄ cycloalkyl, or C₈₋₁₄ heterocycloalkyl; wherein Y² isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of R⁸, OR⁸, SO₂R⁸,CO(O)R⁸, OH, F, Cl, Br and I;

Z¹ is selected from the group consisting of

R², at each occurrence, is independently C₁₋₆ alkyl;

R⁵, at each occurrence, is independently C₁₋₆ alkyl;

R^(6A) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl;

R⁶ and R⁷, at each occurrence, are each independently hydrogen;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl and heterocyclyl; wherein the R⁸C₁₋₆ alkyl isoptionally substituted with one substituent independently selected fromthe group consisting of R¹⁶, OR¹⁶, SO₂R¹⁶, and NHR¹⁶;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇ cycloalkyl andC₁₋₆ haloalkyl;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, aryl, and heterocycloalkyl; wherein theR¹⁶C₁₋₄ alkyl is optionally substituted with one substituentindependently selected from the group consisting of OCH₃, OCH₂CH₂OCH₃,and OCH₂CH₂NHCH₃;

q is 1 or 2;

s is 0;

r is 0 or 1;

wherein the sum of s and r is 0 or 1;

m is 0;

n is 0, 1, or 2;

o is 0, 1, or 2; and

p is 0.

Still another embodiment pertains to a compound having Formula (II)selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-2-methyl-1-[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)ethyl]-1H-pyrrol-3-yl}pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{5-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{5-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]-6-[(cyclopropylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-2-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-2-methyl-1-[(3-methyl-2-oxatricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrrol-3-yl}pyridine-2-carboxylic    acid; and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides compounds of Formula(III)

and therapeutically acceptable salts, metabolites, prodrugs, salts ofmetabolites, and salts of prodrugs thereof, wherein X, L¹, Y², Z¹, R¹,R², R³, m, n, and p are as described herein for Formula (I); R^(x) is asdescribed herein for substituents on Y¹, and o is 0, 1, or 2.

One embodiment of this invention pertains to compounds, andtherapeutically acceptable salts thereof, which are useful as inhibitorsof anti-apoptotic Bcl-xL proteins, the compounds having Formula (III)

wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵,OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₅, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r);

Y² is C₈₋₁₄ cycloalkyl, C₈₋₁₄ cycloalkenyl, C₈₋₁₄ heterocycloalkyl, orC₈₋₁₄ heterocycloalkenyl; optionally fused to one or two rings selectedfrom the group consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene,benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein Y² is optionally substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸,OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸,NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹ at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R¹⁴ and R¹⁴;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, C(O)R¹⁵,CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R¹⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁵)₂,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶, SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, C(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R¹⁶, NR¹⁶S(O)₂R¹⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR¹⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R¹⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R¹⁶)₂, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH₂, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl;

R¹² and R¹³, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of O—(C₁₋₄alkyl), NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O), OH, CN, NO₂, OCF₃,OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6;

o is 0, 1, or 2; and

p is 0, 1, or 2.

In one embodiment of Formula (III), m is 0, 1, 2, or 3; n is 0, 1, 2, 3,4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (III),n is 0, 1, or 2. In another embodiment of Formula (III), n is 0, 1, or2; and each R² is independently deuterium or C₁₋₆ alkyl. In anotherembodiment of Formula (III), m, n, and p are 0.

In one embodiment of Formula (III), X is heteroaryl, which is optionallysubstituted with one, two, three or four R⁴. In another embodiment ofFormula (III), X is heteroaryl, which is unsubstituted. In anotherembodiment of Formula (III), X is heteroaryl, which is substituted withone R⁴. In another embodiment of Formula (III), X is heteroaryl, whichis substituted with two R⁴. In another embodiment of Formula (III), X isheteroaryl, which is substituted with one R⁴, and R⁴ is OR¹² or halogen.In another embodiment of Formula (III), X is heteroaryl, which issubstituted with two R⁴, and each R⁴ is independently OR¹² or halogen.In another embodiment of Formula (III), X is heteroaryl, which issubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (III), X is heteroaryl, which is substituted withtwo R⁴, and each R⁴ is independently F.

In one embodiment of Formula (III), X benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (III), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are unsubstituted. In anotherembodiment of Formula (III), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴. In anotherembodiment of Formula (III), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴. In anotherembodiment of Formula (III), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴, and R⁴ isOR¹² or halogen. In another embodiment of Formula (III), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently OR¹² or halogen. In another embodiment of Formula(III), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which aresubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (III), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently F.

In one embodiment of Formula (III), X is benzo[d]thiazolyl, which isoptionally substituted with one, two, three or four R⁴. In anotherembodiment of Formula (III), X is benzo[d]thiazolyl, which isunsubstituted. In another embodiment of Formula (III), X isbenzo[d]thiazolyl, which is substituted with one R⁴. In anotherembodiment of Formula (III), X is benzo[d]thiazolyl, which issubstituted with two R⁴. In another embodiment of Formula (III), X isbenzo[d]thiazolyl, which is substituted with one R⁴, and R⁴ is OR¹² orhalogen. In another embodiment of Formula (III), X is benzo[d]thiazolyl,which is substituted with two R⁴, and each R⁴ is independently OR¹² orhalogen. In another embodiment of Formula (III), X is benzo[d]thiazolyl,which is substituted with one R⁴, and R⁴ is Cl, F, or methoxy. Inanother embodiment of Formula (III), X is benzo[d]thiazolyl, which issubstituted with two R⁴, and each R⁴ is independently F.

In one embodiment of Formula (III), Z¹ is selected from the groupconsisting of C(O)OR⁹, C(O)NR¹⁰R¹¹, C(O)R¹¹, NR¹⁰C(O)R¹¹,NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹, C(═NOR¹⁰)NR¹⁰R¹¹,NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹, S(O)₂NR¹⁰R¹¹,N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹, C(═NR¹⁰)NR¹⁰R¹¹,halogen, NO₂, and CN; or Z¹ is selected from the group consisting of

In another embodiment of Formula (III), Z¹ is

In another embodiment of Formula (III), Z¹ is

In another embodiment of Formula (III), Z¹ is

In another embodiment of Formula (III), Z¹ is

In one embodiment of Formula (III), o is 0. In another embodiment ofFormula (III), is 0, 1, or 2. In another embodiment of Formula (III), ois 1 or 2; and R^(x), at each occurrence, is independently selected fromthe group consisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵,OC(O)R⁵, OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵,NR⁵S(O)₂R⁵, NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂,NR⁵C(O)NHR⁵, NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH,C(O)NHOR⁵, C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂,CO(O)H, C(O)H, OH, CN, N₅, NO₂, F, Cl, Br and I. In another embodimentof Formula (III), o is 1 or 2; and R^(x), at each occurrence, isindependently selected from the group consisting of R⁵, CN, F, Cl, Brand I. In another embodiment of Formula (III), o is 1 or 2; and R^(x),at each occurrence, is independently selected from the group consistingof R⁵, CN, F, Cl, Br and I; wherein R⁵ is C₁₋₆ alkyl. In anotherembodiment of Formula (III), o is 1 or 2; R^(x) is R⁵, Cl, or CN; and R⁵is CH₃. In another embodiment of Formula (III), o is 1; and R^(x) is CN.In another embodiment of Formula (III), o is 1; and R^(x) is Cl. Inanother embodiment of Formula (III), o is 1; R^(x) is R⁵; and R⁵ is CH₃.

In one embodiment of Formula (III), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is C₈₋₁₄ cycloalkyl, C₈₋₁₄cycloalkenyl, C₈₋₁₄ heterocycloalkyl, or C₈₋₁₄ heterocycloalkenyl;optionally fused to one or two rings selected from the group consistingof C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈heterocycloalkane, and C₃₋₈ heterocycloalkene; wherein Y² is optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I.

In another embodiment of Formula (III), L¹ is (CR⁶R⁷)_(q); and Y² isselected from the group consisting of C₈₋₁₄ cycloalkyl, and C₈₋₁₄heterocycloalkyl; wherein R⁶ and R⁷, at each occurrence, are hydrogen;and q is 1 or 2. In another embodiment of Formula (III), L¹ is selectedfrom the group consisting of (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r); Y² is selected from the groupconsisting of C₈₋₁₄ cycloalkyl, and C₈₋₁₄ heterocycloalkyl; s is 0; r is0 or 1; R^(6A) is independently selected from the group consisting ofhydrogen, and C₁₋₆ alkyl; and R⁶ and R⁷, at each occurrence, arehydrogen.

In another embodiment of Formula (III),

X is heteroaryl;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, CN, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r);

Y² is C₈₋₁₄ cycloalkyl, or C₈₋₁₄ heterocycloalkyl; wherein Y² isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of R⁸, OR⁸, SO₂R⁸,CO(O)R⁸, OH, F, Cl, Br and I;

Z¹ is selected from the group consisting of

R², at each occurrence, is independently C₁₋₆ alkyl;

R⁵, at each occurrence, is independently C₁₋₆ alkyl;

R^(6A) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl;

R⁶ and R⁷, at each occurrence, are each independently hydrogen;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl and heterocyclyl; wherein the R⁸C₁₋₆ alkyl isoptionally substituted with one substituent independently selected fromthe group consisting of R¹⁶, OR¹⁶, SO₂R¹⁶, and NHR¹⁶;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇ cycloalkyl andC₁₋₆ haloalkyl;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, aryl, and heterocycloalkyl; wherein theR¹⁶C₁₋₄ alkyl is optionally substituted with one substituentindependently selected from the group consisting of OCH₃, OCH₂CH₂OCH₃,and OCH₂CH₂NHCH₃;

q is 1 or 2;

s is 0;

r is 0 or 1;

wherein the sum of s and r is 0 or 1;

m is 0;

n is 0, 1, or 2;

o is 0, 1, or 2; and

p is 0.

Still another embodiment pertains to a compound having Formula (III)selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3,5-dimethyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(spiro[3.5]non-7-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-hydroxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(2-methoxyethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5,7-trimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-bromotricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(propan-2-yloxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(morpholin-4-yl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{6-[(methylsulfonyl)carbamoyl]-5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{6-[(cyclopropylsulfonyl)carbamoyl]-5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-(2H-tetrazol-5-yl)pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3-[2-(morpholin-4-yl)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[4,5-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[4,5-c]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(1,1-dioxidothiomorpholin-4-yl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxy-5,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[(morpholin-4-ylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-[5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-{[(trifluoromethyl)sulfonyl]carbamoyl}pyridin-2-yl]-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   N-(1,3-benzothiazol-2-yl)-2-{6-[(cyclopropylsulfonyl)carbamoyl]-5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-chloro-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)(1,1-²H₂)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(2-methoxyethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclooctyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(imidazo[1,2-a]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[2-(2-methoxyethyl)tricyclo[3.3.1.1^(3,7)]dec-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3-[2-(2-methoxyethoxy)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[2-(methylsulfonyl)ethoxy]cyclooctyl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   6-[8-(imidazo[1,2-a]pyrazin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   2-{6-[(methylsulfonyl)carbamoyl]-5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-([1,3]thiazolo[5,4-b]pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(imidazo[1,2-b]pyridazin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(5-methoxyspiro[2.5]oct-5-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(methylsulfonyl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,5-dimethyl-7-[2-(methylamino)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(2-{2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({8-[(benzyloxy)carbonyl]-8-azabicyclo[3.2.1]oct-3-yl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyl-7-(2-{2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl})-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid; and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides compounds of Formula(IV)

and therapeutically acceptable salts, metabolites, prodrugs, salts ofmetabolites, and salts of prodrugs thereof, wherein X, L¹, Y², Z¹, R¹,R², R³, m, n, and p are as described herein for Formula (I); R^(x) is asdescribed herein for substituents on Y¹, and o is 0 or 1.

One embodiment of this invention pertains to compounds, andtherapeutically acceptable salts thereof, which are useful as inhibitorsof anti-apoptotic Bcl-xL proteins, the compounds having Formula (IV)

wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

R^(x) is independently selected from the group consisting of R⁵, OR⁵,SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵, OC(O)OR⁵, NH₂, NHR⁵,N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵, NHC(O)OR⁵,NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₅, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r);

Y² is C₈₋₁₄ cycloalkyl, C₈₋₁₄ cycloalkenyl, C₈₋₁₄ heterocycloalkyl, orC₈₋₁₄ heterocycloalkenyl; optionally fused to one or two rings selectedfrom the group consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene,benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein Y² is optionally substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸,OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸,NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R¹⁴ and R¹⁴;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, C(O)R¹⁵,CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R¹⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁵)₂,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶, SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, C(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R¹⁶, NR¹⁶S(O)₂R¹⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR¹⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R¹⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R¹⁶)₂, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH₂, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl;

R¹² and R¹³, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of O—(C₁₋₄alkyl), NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O), OH, CN, NO₂, OCF₃,OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6;

o is 0 or 1; and

p is 0, 1, or 2.

In one embodiment of Formula (IV), m is 0, 1, 2, or 3; n is 0, 1, 2, 3,4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (IV),n is 0, 1, or 2. In another embodiment of Formula (IV), n is 0, 1, or 2;and each R² is independently deuterium or C₁₋₆ alkyl. In anotherembodiment of Formula (IV), m, n, and p are 0.

In one embodiment of Formula (IV), X is heteroaryl, which is optionallysubstituted with one, two, three or four R⁴. In another embodiment ofFormula (IV), X is heteroaryl, which is unsubstituted. In anotherembodiment of Formula (IV), X is heteroaryl, which is substituted withone R⁴. In another embodiment of Formula (IV), X is heteroaryl, which issubstituted with two R⁴. In another embodiment of Formula (IV), X isheteroaryl, which is substituted with one R⁴, and R⁴ is OR¹² or halogen.In another embodiment of Formula (IV), X is heteroaryl, which issubstituted with two R⁴, and each R⁴ is independently OR¹² or halogen.In another embodiment of Formula (IV), X is heteroaryl, which issubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (IV), X is heteroaryl, which is substituted withtwo R⁴, and each R⁴ is independently F.

In one embodiment of Formula (IV), X benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (IV), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are unsubstituted. In anotherembodiment of Formula (IV), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴. In anotherembodiment of Formula (IV), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴. In anotherembodiment of Formula (IV), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴, and R⁴ isOR¹² or halogen. In another embodiment of Formula (IV), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently OR¹² or halogen. In another embodiment of Formula(IV), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which aresubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (IV), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently F.

In one embodiment of Formula (IV), X is benzo[d]thiazolyl, which isoptionally substituted with one, two, three or four R⁴. In anotherembodiment of Formula (IV), X is benzo[d]thiazolyl, which isunsubstituted. In another embodiment of Formula (IV), X isbenzo[d]thiazolyl, which is substituted with one R⁴. In anotherembodiment of Formula (IV), X is benzo[d]thiazolyl, which is substitutedwith two R⁴. In another embodiment of Formula (IV), X isbenzo[d]thiazolyl, which is substituted with one R⁴, and R⁴ is OR¹² orhalogen. In another embodiment of Formula (IV), X is benzo[d]thiazolyl,which is substituted with two R⁴, and each R⁴ is independently OR¹² orhalogen. In another embodiment of Formula (IV), X is benzo[d]thiazolyl,which is substituted with one R⁴, and R⁴ is Cl, F, or methoxy. Inanother embodiment of Formula (IV), X is benzo[d]thiazolyl, which issubstituted with two R⁴, and each R⁴ is independently F.

In one embodiment of Formula (IV), Z¹ is selected from the groupconsisting of C(O)OR⁹, C(O)NR¹⁰R¹¹, C(O)R¹¹, NR¹⁰C(O)R¹¹,NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹, C(═NOR¹⁰)NR¹⁰R¹¹,NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹, S(O)₂NR¹⁰R¹¹,N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹, C(═NR¹⁰)NR¹⁰R¹¹,halogen, NO₂, and CN; or Z¹ is selected from the group consisting of

In another embodiment of Formula (IV), Z¹ is

In another embodiment of Formula (IV), Z¹ is

In another embodiment of Formula (IV), Z¹ is

In another embodiment of Formula (IV), Z¹ is

In one embodiment of Formula (IV), o is 0. In another embodiment ofFormula (IV), o is 0 or 1. In another embodiment of Formula (IV), o is1; and R^(x) is independently selected from the group consisting of R⁵,OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵, OC(O)OR⁵, NH₂, NHR⁵,N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵, NHC(O)OR⁵,NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₅, NO₂, F, Cl, Br and I. In another embodiment of Formula (IV),o is 1; and R^(x) is independently selected from the group consisting ofR⁵, CN, F, Cl, Br and I. In another embodiment of Formula (IV), o is 1;and R^(x) is independently selected from the group consisting of R⁵, CN,F, Cl, Br and I; wherein R⁵ is C₁₋₆ alkyl. In another embodiment ofFormula (IV), o is 1; R^(x) is R⁵, Cl, or CN; and R⁵ is CH₃. In anotherembodiment of Formula (IV), o is 1; and R^(x) is CN. In anotherembodiment of Formula (IV), o is 1; and R^(x) is Cl. In anotherembodiment of Formula (IV), o is 1; R^(x) is R⁵; and R⁵ is CH₃.

In one embodiment of Formula (IV), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is C₈₋₁₄ cycloalkyl, C₈₋₁₄cycloalkenyl, C₈₋₁₄ heterocycloalkyl, or C₈₋₁₄ heterocycloalkenyl;optionally fused to one or two rings selected from the group consistingof C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈heterocycloalkane, and C₃₋₈ heterocycloalkene; wherein Y² is optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I.

In another embodiment of Formula (IV), L¹ is (CR⁶R⁷)_(q); and Y² isselected from the group consisting of C₈₋₁₄ cycloalkyl and C₈₋₁₄heterocycloalkyl; wherein R⁶ and R⁷, at each occurrence, are hydrogen;and q is 1 or 2. In another embodiment of Formula (IV), L¹ is selectedfrom the group consisting of (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r); Y² is selected from the groupconsisting of C₈₋₁₄ cycloalkyl, and C₈₋₁₄ heterocycloalkyl; s is 0; r is0 or 1; R^(6A) is independently selected from the group consisting ofhydrogen and C₁₋₆ alkyl; and R⁶ and R⁷, at each occurrence, arehydrogen.

In another embodiment of Formula (IV),

X is heteroaryl;

R^(x) is independently selected from the group consisting of R⁵, CN, F,Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r);

Y² is C₈₋₁₄ cycloalkyl or C₈₋₁₄ heterocycloalkyl; wherein Y² isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of R⁸, OR⁸, SO₂R⁸,CO(O)R⁸, OH, F, Cl, Br and I;

Z¹ is selected from the group consisting of

R², at each occurrence, is independently C₁₋₆ alkyl;

R⁵, at each occurrence, is independently C₁₋₆ alkyl;

R^(6A) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl;

R⁶ and R⁷, at each occurrence, are each independently hydrogen;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl and heterocyclyl; wherein the R⁸C₁₋₆ alkyl isoptionally substituted with one substituent independently selected fromthe group consisting of R¹⁶, OR¹⁶, SO₂R¹⁶, and NHR¹⁶;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇ cycloalkyl andC₁₋₆ haloalkyl;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, aryl, and heterocycloalkyl; wherein theR¹⁶C₁₋₄ alkyl is optionally substituted with one substituentindependently selected from the group consisting of OCH₃, OCH₂CH₂OCH₃,and OCH₂CH₂NHCH₃;

q is 1 or 2;

s is O;

r is 0 or 1;

wherein the sum of s and r is 0 or 1;

m is O;

n is 0, 1, or 2;

o is 0 or 1; and

p is 0.

Still another embodiment pertains to a compound having Formula (IV)selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-1,2,3-triazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-1,2,3-triazol-4-yl]pyridine-2-carboxylic    acid; and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides compounds of Formula(V)

and therapeutically acceptable salts, metabolites, prodrugs, salts ofmetabolites, and salts of prodrugs thereof, wherein X, L¹, Y², Z¹, R¹,R², R³, m, n, and p are as described herein for Formula (I); R^(x) is asdescribed herein for substituents on Y¹, and o is 0, 1, 2, 3, or 4.

One embodiment of this invention pertains to compounds, andtherapeutically acceptable salts thereof, which are useful as inhibitorsof anti-apoptotic Bcl-xL proteins, the compounds having Formula (V)

wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵,OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₅, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r);

Y² is C₈₋₁₄ cycloalkyl, C₈₋₁₄ cycloalkenyl, C₈₋₁₄ heterocycloalkyl, orC₈₋₁₄ heterocycloalkenyl; optionally fused to one or two rings selectedfrom the group consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene,benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein Y² is optionally substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸,OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸,NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R¹⁴ and R¹⁴;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, C(O)R¹⁵,CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁵)₂,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶, SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, C(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R¹⁶, NR¹⁶S(O)₂R¹⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR¹⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R¹⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R¹⁶)₂, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH₂, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl;

R¹² and R¹³, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of O—(C₁₋₄alkyl), NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O), OH, CN, NO₂, OCF₃,OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6;

o is 0, 1, 2, 3, or 4; and

p is 0, 1, or 2.

In one embodiment of Formula (V), m is 0, 1, 2, or 3; n is 0, 1, 2, 3,4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (V), nis 0, 1, or 2. In another embodiment of Formula (V), n is 0, 1, or 2;and each R² is independently deuterium or C₁₋₆ alkyl. In anotherembodiment of Formula (V), m, n, and p are 0.

In one embodiment of Formula (V), X is heteroaryl, which is optionallysubstituted with one, two, three or four R⁴. In another embodiment ofFormula (V), X is heteroaryl, which is unsubstituted. In anotherembodiment of Formula (V), X is heteroaryl, which is substituted withone R⁴. In another embodiment of Formula (V), X is heteroaryl, which issubstituted with two R⁴. In another embodiment of Formula (V), X isheteroaryl, which is substituted with one R⁴, and R⁴ is OR¹² or halogen.In another embodiment of Formula (V), X is heteroaryl, which issubstituted with two R⁴, and each R⁴ is independently OR¹² or halogen.In another embodiment of Formula (V), X is heteroaryl, which issubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (V), X is heteroaryl, which is substituted withtwo R⁴, and each R⁴ is independently F.

In one embodiment of Formula (V), X benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (V), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are unsubstituted. In anotherembodiment of Formula (V), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴. In anotherembodiment of Formula (V), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴. In anotherembodiment of Formula (V), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴, and R⁴ isOR¹² or halogen. In another embodiment of Formula (V), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently OR¹² or halogen. In another embodiment of Formula(V), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which aresubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (V), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently F.

In one embodiment of Formula (V), X is benzo[d]thiazolyl, which isoptionally substituted with one, two, three or four R⁴. In anotherembodiment of Formula (V), X is benzo[d]thiazolyl, which isunsubstituted. In another embodiment of Formula (V), X isbenzo[d]thiazolyl, which is substituted with one R⁴. In anotherembodiment of Formula (V), X is benzo[d]thiazolyl, which is substitutedwith two R⁴. In another embodiment of Formula (V), X isbenzo[d]thiazolyl, which is substituted with one R⁴, and R⁴ is OR¹² orhalogen. In another embodiment of Formula (V), X is benzo[d]thiazolyl,which is substituted with two R⁴, and each R⁴ is independently OR¹² orhalogen. In another embodiment of Formula (V), X is benzo[d]thiazolyl,which is substituted with one R⁴, and R⁴ is Cl, F, or methoxy. Inanother embodiment of Formula (V), X is benzo[d]thiazolyl, which issubstituted with two R⁴, and each R⁴ is independently F.

In one embodiment of Formula (V), Z¹ is selected from the groupconsisting of C(O)OR⁹, C(O)NR¹⁰R¹¹, C(O)R¹¹, NR¹⁰C(O)R¹¹,NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹, C(═NOR¹⁰)NR¹⁰R¹¹,NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹, S(O)₂NR¹⁰R¹¹,N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹, C(═NR¹⁰)NR¹⁰R¹¹,halogen, NO₂, and CN; or Z¹ is selected from the group consisting of

In another embodiment of Formula (V), Z¹ is

In another embodiment of Formula (V), Z is

In another embodiment of Formula (V), Z¹ is

In another embodiment of Formula (V), Z¹ is

In one embodiment of Formula (V), o is 0. In another embodiment ofFormula (V), o is 0, 1, 2, 3, or 4. In another embodiment of Formula(V), o is 1, 2, 3, or 4; and R^(x), at each occurrence, is independentlyselected from the group consisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵,C(O)R⁵, CO(O)R⁵, OC(O)R⁵, OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵,NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵, NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂,NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵, NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵,C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵, C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂,SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H, OH, CN, N₅, NO₂, F, Cl, Br and I. Inanother embodiment of Formula (V), o is 1, 2, 3, or 4; and R^(x), ateach occurrence, is independently selected from the group consisting ofR⁵, CN, F, Cl, Br and I. In another embodiment of Formula (V), o is 1,2, 3, or 4; and R^(x), at each occurrence, is independently selectedfrom the group consisting of R⁵, CN, F, Cl, Br and I; wherein R⁵ is C₁₋₆alkyl. In another embodiment of Formula (V), o is 1 or 2; R^(x) is R⁵ orCN; and R⁵ is CH₃. In another embodiment of Formula (V), o is 1; andR^(x) is CN. In another embodiment of Formula (V), o is 1; and R^(x) isCl. In another embodiment of Formula (V), o is 1; R^(x) is R⁵; and R⁵ isCH₃.

In one embodiment of Formula (V), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is C₈₋₁₄ cycloalkyl, C₈₋₁₄cycloalkenyl, C₈₋₁₄ heterocycloalkyl, or C₈₋₁₄ heterocycloalkenyl;optionally fused to one or two rings selected from the group consistingof C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈heterocycloalkane, and C₃₋₈ heterocycloalkene; wherein Y² is optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I.

In another embodiment of Formula (V), L¹ is (CR⁶R⁷)_(q); and Y² isselected from the group consisting of C₈₋₁₄ cycloalkyl, and C₈₋₁₄heterocycloalkyl; wherein R⁶ and R⁷, at each occurrence, are hydrogen;and q is 1 or 2. In another embodiment of Formula (V), L¹ is selectedfrom the group consisting of (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r); Y² is selected from the groupconsisting of C₈₋₁₄ cycloalkyl, and C₈₋₁₄ heterocycloalkyl; s is 0; r is0 or 1; R^(6A) is independently selected from the group consisting ofhydrogen, and C₁₋₆ alkyl; and R⁶ and R⁷, at each occurrence, arehydrogen.

In another embodiment of Formula (V),

X is heteroaryl;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, CN, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r),(CR⁶R⁷))_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),and (CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r);

Y² is C₈₋₁₄ cycloalkyl, or C₈₋₁₄ heterocycloalkyl; wherein Y² isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of R⁸, OR⁸, SO₂R⁸,CO(O)R⁸, OH, F, Cl, Br and I;

Z¹ is selected from the group consisting of

-   -   R², at each occurrence, is independently C₁₋₆ alkyl;

R⁵, at each occurrence, is independently C₁₋₆ alkyl;

R^(6A) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl;

R⁶ and R⁷, at each occurrence, are each independently hydrogen;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl and heterocyclyl; wherein the R⁸C₁₋₆ alkyl isoptionally substituted with one substituent independently selected fromthe group consisting of R¹⁶, OR¹⁶, SO₂R¹⁶, and NHR¹⁶;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇ cycloalkyl andC₁₋₆ haloalkyl;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, aryl, and heterocycloalkyl; wherein theR¹⁶C₁₋₄ alkyl is optionally substituted with one substituentindependently selected from the group consisting of OCH₃, OCH₂CH₂OCH₃,and OCH₂CH₂NHCH₃;

q is 1 or 2;

s is 0;

r is 0 or 1;

wherein the sum of s and r is 0 or 1;

m is O;

n is 0, 1, or 2;

o is 0 or 1; and

p is 0.

Still another embodiment pertains to a compound having Formula (V)selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-4-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl})pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-yloxy]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylamino]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfamoyl]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbamoyl]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]amino}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-cyano-3-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfonyl)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[(tricyclo[3.3.1.1^(3,7)]dec-2-yl]carbamoyl}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl)amino]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-2-yl]sulfamoyl}phenyl)pyridine-2-carboxylic    acid; and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides compounds of Formula(VI)

and therapeutically acceptable salts, metabolites, prodrugs, salts ofmetabolites, and salts of prodrugs thereof, wherein X, L¹, Y², Z¹, R¹,R², R³, m, n, and p are as described herein for Formula (I); R^(x) is asdescribed herein for substituents on Y¹, and o is 0, 1, 2, or 3.

One embodiment of this invention pertains to compounds, andtherapeutically acceptable salts thereof, which are useful as inhibitorsof anti-apoptotic Bcl-xL proteins, the compounds having Formula (VI)

wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵,OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₅, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r);

Y² is C₈₋₁₄ cycloalkyl, C₈₋₁₄ cycloalkenyl, C₈₋₁₄ heterocycloalkyl, orC₈₋₁₄ heterocycloalkenyl; optionally fused to one or two rings selectedfrom the group consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene,benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein Y² is optionally substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸,OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸,NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R¹⁴ and R¹⁴;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, C(O)R¹⁵,CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R¹⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁵)₂,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶, SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, C(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R¹⁶, NR¹⁶S(O)₂R¹⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR¹⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R¹⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R¹⁶)₂, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH₂, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl;

R¹² and R¹³, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of O—(C₁₋₄alkyl), NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O), OH, CN, NO₂, OCF₃,OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6;

o is 0, 1, 2, or 3; and

p is 0, 1, or 2.

In one embodiment of Formula (VI), m is 0, 1, 2, or 3; n is 0, 1, 2, 3,4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (VI),n is 0, 1, or 2. In another embodiment of Formula (VI), n is 0, 1, or 2;and each R² is independently deuterium or C₁₋₆ alkyl. In anotherembodiment of Formula (VI), m, n, and p are 0.

In one embodiment of Formula (VI), X is heteroaryl, which is optionallysubstituted with one, two, three or four R⁴. In another embodiment ofFormula (VI), X is heteroaryl, which is unsubstituted. In anotherembodiment of Formula (VI), X is heteroaryl, which is substituted withone R⁴. In another embodiment of Formula (VI), X is heteroaryl, which issubstituted with two R⁴. In another embodiment of Formula (VI), X isheteroaryl, which is substituted with one R⁴, and R⁴ is OR¹² or halogen.In another embodiment of Formula (VI), X is heteroaryl, which issubstituted with two R⁴, and each R⁴ is independently OR¹² or halogen.In another embodiment of Formula (VI), X is heteroaryl, which issubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (VI), X is heteroaryl, which is substituted withtwo R⁴, and each R⁴ is independently F.

In one embodiment of Formula (VI), X benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (VI), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are unsubstituted. In anotherembodiment of Formula (VI), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴. In anotherembodiment of Formula (VI), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴. In anotherembodiment of Formula (VI), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴, and R⁴ isOR¹² or halogen. In another embodiment of Formula (VI), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently OR¹² or halogen. In another embodiment of Formula(VI), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which aresubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (VI), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently F.

In one embodiment of Formula (VI), X is benzo[d]thiazolyl, which isoptionally substituted with one, two, three or four R⁴. In anotherembodiment of Formula (VI), X is benzo[d]thiazolyl, which isunsubstituted. In another embodiment of Formula (VI), X isbenzo[d]thiazolyl, which is substituted with one R⁴. In anotherembodiment of Formula (VI), X is benzo[d]thiazolyl, which is substitutedwith two R⁴. In another embodiment of Formula (VI), X isbenzo[d]thiazolyl, which is substituted with one R⁴, and R⁴ is OR¹² orhalogen. In another embodiment of Formula (VI), X is benzo[d]thiazolyl,which is substituted with two R⁴, and each R⁴ is independently OR¹² orhalogen. In another embodiment of Formula (VI), X is benzo[d]thiazolyl,which is substituted with one R⁴, and R⁴ is Cl, F, or methoxy. Inanother embodiment of Formula (VI), X is benzo[d]thiazolyl, which issubstituted with two R⁴, and each R⁴ is independently F.

In one embodiment of Formula (VI), Z¹ is selected from the groupconsisting of C(O)OR⁹, C(O)NR¹⁰R¹¹, C(O)R¹¹, NR¹⁰C(O)R¹¹,NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹, C(═NOR¹⁰)NR¹⁰R¹¹,NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹, S(O)₂NR¹⁰R¹¹,N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹, C(═NR¹⁰)NR¹⁰R¹¹,halogen, NO₂, and CN; or Z¹ is selected from the group consisting of

In another embodiment of Formula (VI), Z¹ is

In another embodiment of Formula (VI), Z¹ is

In another embodiment of Formula (VI), Z¹ is

In another embodiment of Formula (VI), Z¹¹ is

In one embodiment of Formula (VI), o is 0. In another embodiment ofFormula (VI), is 0, 1, 2, or 3. In another embodiment of Formula (VI), ois 1, 2, or 3; and R^(x), at each occurrence, is independently selectedfrom the group consisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵,CO(O)R⁵, OC(O)R⁵, OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵,NHS(O)₂R⁵, NR⁵S(O)₂R⁵, NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵,NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵, NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂,C(O)NHOH, C(O)NHOR⁵, C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵,SO₂N(R⁵)₂, CO(O)H, C(O)H, OH, CN, N₅, NO₂, F, Cl, Br and I. In anotherembodiment of Formula (VI), o is 1, 2, or 3; and R^(x), at eachoccurrence, is independently selected from the group consisting of R⁵,CN, F, Cl, Br and I. In another embodiment of Formula (VI), o is 1, 2,or 3; and R^(x), at each occurrence, is independently selected from thegroup consisting of R⁵, CN, F, Cl, Br and I; wherein R⁵ is C₁₋₆ alkyl.In another embodiment of Formula (VI), o is 1 or 2; R^(x) is R⁵ or CN;and R⁵ is CH₃. In another embodiment of Formula (VI), o is 1; and R^(x)is CN. In another embodiment of Formula (VI), o is 1; and R^(x) is Cl.In another embodiment of Formula (VI), o is 1; R^(x) is R⁵; and R⁵ isCH₃.

In one embodiment of Formula (VI), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is C₈₋₁₄ cycloalkyl, C₈₋₁₄cycloalkenyl, C₈₋₁₄ heterocycloalkyl, or C₈₋₁₄ heterocycloalkenyl;optionally fused to one or two rings selected from the group consistingof C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈heterocycloalkane, and C₃₋₈ heterocycloalkene; wherein Y² is optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I.

In another embodiment of Formula (VI), L¹ is (CR⁶R⁷)_(q); and Y² isselected from the group consisting of C₈₋₁₄ cycloalkyl, and C₈₋₁₄heterocycloalkyl; wherein R⁶ and R⁷, at each occurrence, are hydrogen;and q is 1 or 2. In another embodiment of Formula (VI), L¹ is selectedfrom the group consisting of (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)C(O)NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r); Y² is selected from the groupconsisting of C₈₋₁₄ cycloalkyl, and C₈₋₁₄ heterocycloalkyl; s is 0; r is0 or 1; R^(6A) is independently selected from the group consisting ofhydrogen, and C₁₋₆ alkyl; and R⁶ and R⁷, at each occurrence, arehydrogen.

In another embodiment of Formula (VI),

X is heteroaryl;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, CN, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),and (CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r);

Y² is C₈₋₁₄ cycloalkyl, or C₈₋₁₄ heterocycloalkyl; wherein Y² isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of R⁸, OR⁸, SO₂R⁸,CO(O)R⁸, OH, F, Cl, Br and I;

Z¹ is selected from the group consisting of

R², at each occurrence, is independently C₁₋₆ alkyl;

R⁵, at each occurrence, is independently C₁₋₆ alkyl;

R^(6A) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl;

R⁶ and R⁷, at each occurrence, are each independently hydrogen;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl and heterocyclyl; wherein the R⁸C₁₋₆ alkyl isoptionally substituted with one substituent independently selected fromthe group consisting of R¹⁶, OR¹⁶, SO₂R¹⁶, and NHR¹⁶;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇ cycloalkyl andC₁₋₆ haloalkyl;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, aryl, and heterocycloalkyl; wherein theR¹⁶C₁₋₄ alkyl is optionally substituted with one substituentindependently selected from the group consisting of OCH₃, OCH₂CH₂OCH₃,and OCH₂CH₂NHCH₃;

q is 1 or 2;

s is O;

r is 0 or 1;

wherein the sum of s and r is 0 or 1;

m is O;

n is 0, 1, or 2;

o is 0 or 1; and

p is 0.

Still another embodiment pertains to a compound having Formula (VI)selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-[cyclooctyl(methyl)amino]-3′-methyl-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfonyl)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylamino)-3,4′-bipyridine-2-carboxylic    acid; and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.    Pharmaceutical Compositions, Combination Therapies, Methods of    Treatment, and Administration

Another embodiment comprises pharmaceutical compositions comprising acompound having Formula (I) and an excipient.

Still another embodiment comprises methods of treating cancer in amammal comprising administering thereto a therapeutically acceptableamount of a compound having Formula (I).

Still another embodiment comprises methods of treating autoimmunedisease in a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseasesduring which anti-apoptotic Bcl-xL proteins are expressed, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (I).

Still another embodiment pertains to methods of treating disease in apatient during which anti-apoptotic Bcl-xL proteins are expressed, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, prostate cancer, small cell lung cancer or spleencancer, said compositions comprising an excipient and a therapeuticallyeffective amount of the compound having Formula (I).

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, prostate cancer, small cell lung cancer or spleen cancer in apatient, said methods comprising administering to the patient atherapeutically effective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseasesduring which are expressed anti-apoptotic Bcl-xL proteins, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (I) and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to methods of treating disease in apatient during which are expressed anti-apoptotic Bcl-xL proteins, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound having Formula (I) and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositionscomprising an excipient and a therapeutically effective amount of thecompound having Formula (I) and a therapeutically effective amount ofone additional therapeutic agent or more than one additional therapeuticagent.

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said methods comprisingadministering to the patient a therapeutically effective amount of thecompound having Formula (I) and a therapeutically effective amount ofone additional therapeutic agent or more than one additional therapeuticagent.

Metabolites of compounds having Formula (I), produced by in vitro or invivo metabolic processes, may also have utility for treating diseasesassociated with anti-apoptotic Bcl-xL proteins.

Certain precursor compounds which may be metabolized in vitro or in vivoto form compounds having Formula (I) may also have utility for treatingdiseases associated with expression of anti-apoptotic Bcl-xL proteins.

Compounds having Formula (I) may exist as acid addition salts, basicaddition salts or zwitterions. Salts of the compounds are preparedduring isolation or following purification of the compounds. Acidaddition salts of the compounds are those derived from the reaction ofthe compounds with an acid. For example, the acetate, adipate, alginate,bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate, formate, fumarate,glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate,maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate,propionate, succinate, tartrate, thiocyanate, trichloroacetic,trifluoroacetic, para-toluenesulfonate, and undecanoate salts of thecompounds are contemplated as being embraced by this invention. Basicaddition salts of the compounds are those derived from the reaction ofthe compounds with the hydroxide, carbonate or bicarbonate of cationssuch as lithium, sodium, potassium, calcium, and magnesium.

The compounds having Formula (I) may be administered, for example,bucally, ophthalmically, orally, osmotically, parenterally(intramuscularly, intraperitoneally intrasternally, intravenously,subcutaneously), rectally, topically, transdermally or vaginally.

Therapeutically effective amounts of compounds having Formula (I) dependon the recipient of the treatment, the disorder being treated and theseverity thereof, the composition containing the compound, the time ofadministration, the route of administration, the duration of treatment,the compound potency, its rate of clearance and whether or not anotherdrug is co-administered. The amount of a compound of this inventionhaving Formula (I) used to make a composition to be administered dailyto a patient in a single dose or in divided doses is from about 0.03 toabout 200 mg/kg body weight. Single dose compositions contain theseamounts or a combination of submultiples thereof.

Compounds having Formula (I) may be administered with or without anexcipient. Excipients include, for example, encapsulating materials oradditives such as absorption accelerators, antioxidants, binders,buffers, coating agents, coloring agents, diluents, disintegratingagents, emulsifiers, extenders, fillers, flavoring agents, humectants,lubricants, perfumes, preservatives, propellants, releasing agents,sterilizing agents, sweeteners, solubilizers, wetting agents andmixtures thereof.

Excipients for preparation of compositions comprising a compound havingFormula (I) to be administered orally in solid dosage form include, forexample, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzylbenzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose,cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil,cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate,ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonicsaline, lactose, magnesium hydroxide, magnesium stearate, malt,mannitol, monoglycerides, olive oil, peanut oil, potassium phosphatesalts, potato starch, povidone, propylene glycol, Ringer's solution,safflower oil, sesame oil, sodium carboxymethyl cellulose, sodiumphosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil,stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth,tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered ophthalmically or orallyin liquid dosage forms include, for example, 1,3-butylene glycol, castoroil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan,germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethyleneglycols, propylene glycol, sesame oil, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered osmotically include, forexample, chlorofluorohydrocarbons, ethanol, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered parenterally include,for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil,dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil,peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil,U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered rectally or vaginallyinclude, for example, cocoa butter, polyethylene glycol, wax andmixtures thereof.

Compounds having Formula (I) are expected to be useful when used withalkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors,other apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1)inhibitors, activators of death receptor pathway, Bcr-Abl kinaseinhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drugconjugates, biologic response modifiers, cyclin-dependent kinaseinhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs,leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growthfactor inhibitors, heat shock protein (HSP)-90 inhibitors, histonedeacetylase (HDAC) inhibitors, hormonal therapies, immunologicals,inhibitors of inhibitors of apoptosis proteins (IAPs), intercalatingantibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors,mammalian target of rapamycin inhibitors, microRNA's, mitogen-activatedextracellular signal-regulated kinase inhibitors, multivalent bindingproteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP(adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinumchemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs,pyrimidine analogs, receptor tyrosine kinase inhibitors,retinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids(siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and thelike, and in combination with one or more of these agents.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies includeadecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and thelike. Without being limited by theory, one of the mechanisms by whichT-cells elicit apoptosis of the target cancer cell is by exocytosis ofcytolytic granule components, which include perforin and granzyme B.

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′- and/or the3′-ends of a given strand. For example, siRNAs targeting Mcl-1 have beenshown to enhance the activity of ABT-263, (i.e.,N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide)or ABT-737 (i.e.,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)in multiple tumor cell lines (Tse et. al, Cancer Research 2008, 68(9),3421 and references therein).

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide,decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide,KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol,mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine,temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamideand the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitorsand pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((−)gossypol), GENASENSE® (G3139or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194,IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax) and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine,EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA®(gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusionprotein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her2IgG3, AS HER2 trifunctional bispecific antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FCl, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35,SGN-75 and the like

Activators of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death receptors (e.g., DR4 and DR5) such asApomab, conatumumab, ETR2-ST01, GDC0145 (lexatumumab), HGS-1029,LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(etodolac), TORADOL® (ketorolac), DAYPRO®(oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474) and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,epirbucin, glarbuicin, ZAVEDOS®(idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20antibodies types I and II and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™(fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate,MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH 1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1,combinations thereof and the like. Other agents include ALFAFERONE®,(IFN-α), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR®(tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyteantigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™(gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX®(oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T),sargaramostim, sizofilan, teceleukin, THERACYS® (BacillusCalmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, LorusPharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10(Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomabtiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofuran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins,NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers thatenhance the efficacy of radiotherapy. Examples of radiotherapy includeexternal beam radiotherapy, teletherapy, brachytherapy and sealed,unsealed source radiotherapy and the like.

Additionally, compounds having Formula (I) may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA),APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin,L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene),AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine),CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EP0906 (epithilone B), GARDASIL® (quadrivalent human papillomavirus(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®,GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine),halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101,IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zorubicin and the like.

Data

Determination of the utility of compounds having Formula (I) as bindersto and inhibitors of anti-apoptotic Bcl-xL proteins was performed usingthe Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET)Assay. Tb-anti-GST antibody was purchased from Invitrogen (Catalog No.PV4216).

Probe Synthesis

All reagents were used as obtained from the vendor unless otherwisespecified. Peptide synthesis reagents including diisopropylethylamine(DIEA), dichloromethane (DCM), N-methylpyrrolidone (NMP),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), N-hydroxybenzotriazole (HOBt) and piperidine were obtained fromApplied Biosystems, Inc. (ABI), Foster City, Calif. or AmericanBioanalytical, Natick, Mass. Preloaded 9-Fluorenylmethyloxycarbonyl(Fmoc) amino acid cartridges (Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH,Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Phe-OH, Fmoc-Gly-OH,Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH,Fmoc-Met-OH, Fmoc-Asn(Trt)-OH, Fmoc-Pro-OH, Fmor-Gln(Trt)-OH,Fmoc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH,Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH) were obtained from ABI or Anaspec,San Jose, Calif. The peptide synthesis resin (Fmoc-Rink amide MBHAresin) and Fmoc-Lys(Mtt)-OH were obtained from Novabiochem, San Diego,Calif. Single-isomer 6-carboxyfluorescein succinimidyl ester (6-FAM-NHS)was obtained from Anaspec. Trifluoroacetic acid (TFA) was obtained fromOakwood Products, West Columbia, S.C. Thioanisole, phenol,triisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol (DODT) andisopropanol were obtained from Aldrich Chemical Co., Milwaukee, Wis.Matrix-assisted laser desorption ionization mass-spectra (MALDI-MS) wererecorded on an Applied Biosystems Voyager DE-PRO MS). Electrospraymass-spectra (ESI-MS) were recorded on Finnigan SSQ7000 (Finnigan Corp.,San Jose, Calif.) in both positive and negative ion mode.

General Procedure for Solid-Phase Peptide Synthesis (SPPS)

Peptides were synthesized with, at most, 250 mol preloaded Wangresin/vessel on an ABI 433A peptide synthesizer using 250 mol scaleFastmoc™ coupling cycles. Preloaded cartridges containing 1 mmolstandard Fmoc-amino acids, except for the position of attachment of thefluorophore, where 1 mmol Fmoc-Lys(Mtt)-OH was placed in the cartridge,were used with conductivity feedback monitoring. N-terminal acetylationwas accomplished by using 1 mmol acetic acid in a cartridge understandard coupling conditions.

Removal of 4-Methyltrityl (Mtt) from Lysine

The resin from the synthesizer was washed thrice with dichloromethaneand kept wet. 150 mL of 95:4:1dichloromethane:triisopropylsilane:trifluoroacetic acid was flowedthrough the resin bed over 30 minutes. The mixture turned deep yellowthen faded to pale yellow. 100 mL of DMF was flowed through the bed over15 minutes. The resin was then washed thrice with DMF and filtered.Ninhydrin tests showed a strong signal for primary amine.

Resin Labeling with 6-Carboxyfluorescein-NHS (6-FAM-NHS)

The resin was treated with 2 equivalents 6-FAM-NHS in 1% DIEA/DMF andstirred or shaken at ambient temperature overnight. When complete, theresin was drained, washed thrice with DMF, thrice with (1×dichloromethane and 1× methanol) and dried to provide an orange resinthat was negative by ninhydrin test.

General Procedure for Cleavage and Deprotection of Resin-Bound Peptide

Peptides were cleaved from the resin by shaking for 3 hours at ambienttemperature in a cleavage cocktail consisting of 80% TFA, 5% water, 5%thioanisole, 5% phenol, 2.5% TIS, and 2.5% EDT (1 mL/0.1 g resin). Theresin was removed by filtration and rinsing twice with TFA. The TFA wasevaporated from the filtrates, and product was precipitated with ether(10 mL/0.1 g resin), recovered by centrifugation, washed twice withether (10 mL/0.1 g resin) and dried to give the crude peptide.

General Procedure for Purification of Peptides

The crude peptides were purified on a Gilson preparative HPLC systemrunning Unipoint® analysis software (Gilson, Inc., Middleton, Wis.) on aradial compression column containing two 25×100 mm segments packed withDelta-Pak™ C18 15 μm particles with 100 Å pore size and eluted with oneof the gradient methods listed below. One to two milliliters of crudepeptide solution (10 mg/mL in 90% DMSO/water) was purified perinjection. The peaks containing the product(s) from each run were pooledand lyophilized. All preparative runs were run at 20 mL/min with eluentsas buffer A: 0.1% TFA-water and buffer B: acetonitrile.

General Procedure for Analytical HPLC

Analytical HPLC was performed on a Hewlett-Packard 1200 series systemwith a diode-array detector and a Hewlett-Packard 1046A fluorescencedetector running HPLC 3D ChemStation software version A.03.04(Hewlett-Packard. Palo Alto, Calif.) on a 4.6×250 mm YMC column packedwith ODS-AQ 5 μm particles with a 120 Å pore size and eluted with one ofthe gradient methods listed below after preequilibrating at the startingconditions for 7 minutes. Eluents were buffer A: 0.1% TFA-water andbuffer B: acetonitrile. The flow rate for all gradients was 1 mL/min.

F-Bak: Peptide Probe Acetyl-(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)-(SEQ IDNO: 2)INR-NH₂

Fmoc-Rink amide MBHA resin was extended using the general peptidesynthesis procedure to provide the protected resin-bound peptide (1.020g). The Mtt group was removed, labeled with 6-FAM-NHS and cleaved anddeprotected as described hereinabove to provide the crude product as anorange solid (0.37 g). This product was purified by RP-HPLC. Fractionsacross the main peak were tested by analytical RP-HPLC, and the purefractions were isolated and lyophilized, with the major peak providingthe title compound (0.0802 g) as a yellow solid; MALDI-MS m/z=2137.1[(M+H)⁺].

Alternative Synthesis of Peptide Probe F-Bak: Acetyl-(SEQ ID NO:1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO:2)INR-NH₂

The protected peptide was assembled on 0.25 mmol Fmoc-Rink amide MBHAresin (Novabiochem) on an Applied Biosystems 433A automated peptidesynthesizer running Fastmoc™ coupling cycles using pre-loaded 1 mmolamino acid cartridges, except for the fluorescein(6-FAM)-labeled lysine,where 1 mmol Fmoc-Lys(4-methyltrityl) was weighed into the cartridge.The N-terminal acetyl group was incorporated by putting 1 mmol aceticacid in a cartridge and coupling as described hereinabove. Selectiveremoval of the 4-methyltrityl group was accomplished with a solution of95:4:1 DCM:TIS:TFA (v/v/v) flowed through the resin over 15 minutes,followed by quenching with a flow of dimethylformamide. Single-isomer6-carboxyfluorescein-NHS was reacted with the lysine side-chain in 1%DIEA in DMF and confirmed complete by ninhydrin testing. The peptide wascleaved from the resin and side-chains deprotected by treating with80:5:5:5:2.5:2.5 TFA/water/phenol/thioanisole/triisopropylsilane:3,6-dioxa-1,8-octanedithiol (v/v/v/v/v/v), and the crude peptide wasrecovered by precipitation with diethyl ether. The crude peptide waspurified by reverse-phase high-performance liquid chromatography, andits purity and identity were confirmed by analytical reverse-phasehigh-performance liquid chromatography and matrix-assistedlaser-desorption mass-spectrometry (m/z=2137.1 ((M+H)⁺).

Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay

The measurement of competition of compounds of the invention with F-Bakfor a Bcl-2 family protein (Bcl-xL) binding site using a Time ResolvedFluorescence Resonance Energy Transfer (TR-FRET) binding assay:

Test compounds were serially diluted in DMSO starting at 50 M (2×starting concentration; 10% DMSO) and 10 μL transferred into a 384-wellplate. Then 10 μL of a protein/probe/antibody mix is added to each wellat final concentrations listed in Table 1.

TABLE 1  Anti- Protein Probe Anti- body Protein Probe (nM) (nM) body(nM) GST-Bcl- F-Bak  1 100 Tb-anti- 1 xL (GQVGRQLAIIGDK GST (6-FAM)INR-amide)

The samples are then mixed on a shaker for 1 minute then incubated foran additional 2 hours at room temperature. For each assay plate, aprobe/antibody and protein/antibody/probe mixture were included as anegative and a positive control, respectively. Fluorescence was measuredon the Envision (Perkin Elmer) using a 340/35 nm excitation filter and520/525 (F-Bak) and 495/510 nm (Tb-labeled anti-his antibody) emissionfilters. Dissociation constants (K_(i)) were determined using Wang'sequation (Wang, Z. X. An exact mathematical expression for describingcompetitive binding of two different ligands to a protein molecule. FEBSLett. 1995 360:111-114). The TR-FRET assay can be performed in thepresence of varying concentrations of human serum (HS) or fetal bovineserum (FBS). TR-FRET assay results (K_(i) in nanomolar) forrepresentative compounds of Formula (I) set forth in Table 2 areprovided below in Table 2.

For comparison, the measurement of the competition of compounds ofFormula (I) for other Bcl-2 family protein binding sites (e.g., Bcl-2)using the TR-FRET binding assay was accomplished by substitutingGST-Bcl-xL in the TR-FRET assay with other GST-labeled protein, e.g.,GST-Bcl-2, prepared in-house.

In one embodiment, compounds of Formula (I) selectively inhibit theBcl-2 family protein, Bcl-xL, over other Bcl-2 family proteins, such asBcl-2. For comparison, data (K_(i) in micromolar) from the measurementof the competition by certain compounds of Formula (I) (i.e., Examples3, 23, 45, 52 and 59 in Table 3) with F-Bak for the Bcl-2 binding siteusing the TR-FRET binding assay are 0.007, 0.016, 0.010, 0.104, and0.007 respectively.

FL5.12 Cellular Assay

The efficacy of compounds of Formula (I) can also be determined incell-based killing assays using a variety of cell lines and mouse tumormodels. For example, their activity on cell viability can be assessed ona panel of cultured tumorigenic and non-tumorigenic cell lines, as wellas primary mouse or human cell populations. In one exemplary set ofconditions, mouse FL5.12 cells transfected with Bcl-xL were culturedunder standard conditions in RPMI with 2 mM glutamine, 1% 100 mM sodiumpyruvate, 2% 1 M HEPES, 4 μL/L of 3-mercaptoethanol, 1%penicillin-streptomycin, 10% FBS, and 10% WEHI-3B conditioned media (forIL-3). For assaying the compound activity, the cells were exchanged intoan IL-3-depleted deprivation media, which was identical to the growthmedia except for the absence of FBS and WEHI-3B conditional media, for 2days. Then the cells were exchanged to 3% FBS assay media (RPMI with 2mM glutamine, 1% 100 mM sodium pyruvate, 2% 1 M HEPES, 4 μL/L of3-mercaptoethanol, 1% penicillin-streptomycin, 3% FBS). Compounds inseries dilutions were added, and the cells were cultured for 24 hours.Compounds in series dilutions were added, and the cells were culturedfor 24 hurs. Cell viability was assayed using the CellTiter-Glo assay(Promega Corp., Madison, Wis.) according to the manufacturerinstructions. Individual determinations were the result of duplicatevalues. Cell viability assay results (EC₅₀ in nanomolar) forrepresentative Examples are provided below in Table 2.

TABLE 2 In Vitro Data TR-FRET binding FL5.12 Bcl-xL, EX Bcl-xL Ki (nM)-IL3, EC₅₀ (nM) 1 <0.1 39 2 <0.1 <1 3 <0.1 <1 4 0.5 918 5 <0.1 2 6 <0.1146 7 <0.1 37 8 <0.1 147 9 0.2 3 10 <0.1 29 11 <0.1 11 12 <0.1 24 13<0.1 71 14 0.2 <1 15 <0.1 110 16 <0.1 <1 17 <0.1 1 18 <0.1 1 19 0.1 3 204 >1000 21 0.6 343 22 1 >1000 23 <0.1 <1 24 <0.1 <1 25 0.8 >1000 26 n.d.243 27 0.1 214 28 0.5 22 29 <0.1 3 30 <0.1 49 31 <0.1 5 32 <0.1 1 330.1 >1000 34 0.4 150 35 <0.1 1 36 0.3 0.8 37 <0.1 3 38 <0.1 0.1 39 120.6 40 0.1 47 41 <0.1 0.4 42 0.3 0.5 43 0.2 9 44 <0.1 0.3 43 0.2 9 44<0.1 0.3 45 <0.1 0.9 46 <0.1 1 47 0.2 54 48 0.2 8 49 <0.1 5 50 9 >100051 0.3 164 52 0.2 3 53 <0.1 4 54 2 >1000 55 0.4 47 56 <0.1 17 57 <0.1 1258 <0.1 0.3 59 <0.1 0.3 60 <0.1 55 61 <0.1 10 62 <0.1 0.8 63 <0.1 3 64<0.1 26 65 <0.1 1 66 <0.1 26 67 <0.1 9 68 <0.1 22 69 0.6 449 70 <0.1 7271 <0.1 1 72 <0.1 0.2 73 <0.1 n.d. 74 <0.1 7 75 <0.1 3 76 <0.1 71 77<0.1 4 78 <0.1 3 79 <0.1 0.9 80 <0.1 1 81 <0.1 n.d 82 <0.1 n.d. 83 <0.1n.d. 84 0.9 >1000 85 <0.1 111 n.d. = no data available

Molt-4 Cellular Assay

Molt-4 (ATCC, Manassas, Va.) human acute lymphoblastic leukemia cellswere plated 50,000 cells per well in 96-well tissue culture plates in atotal volume of 100 μL tissue culture medium supplemented with 10% humanserum (Invitrogen, Carlsbad, Calif.) and treated with a 3-fold serialdilution of the compounds of interest from 5 μM to 0.020 μL. Eachconcentration was tested in duplicate at least 3 separate times. Thenumber of viable cells following 48 hours of compound treatment wasdetermined using the CellTiter 96® Aqueous non-radioactive cellproliferation MTS assay according to manufacturer's recommendations(Promega Corp., Madison, Wis.). Molt-4 cell viability results (i.e. EC₅₀in micromolar) for certain compounds of Formula (I), i.e., Examples 1,3, 10, 18, 23, 28, 45, 52, 59, and 72 in Table 2, are 0.201, 0.006,0.487, 0.024, 0.016, 0.526, 0.004, 0.029, 0.024, and 0.035 respectively.

Single Dose Pharmacokinetics

The single dose pharmacokinetics of select compounds were evaluated inSprague-Dawley rats (Charles River) after a 5 mg/kg oral dose (n=3) (10%DMSO in PEG-400) administered by gavage or by 5 mg/kg IV bolus dose(n=3) (10% DMSO in PEG-400). Compound and the internal standard wereseparated from each other and coextracted contaminants on a 50 mm×3 mmKeystone Betasil CN 5 μm column with an acetonitrile/0.1%trifluoroacetic acid mobile phase (50:50, by volume) at a flow rate of0.7 mL/min. Analysis was performed on a Sciex API3000 biomolecular massanalyzer with a heated nebulizer interface. Compound and internalstandard peak areas were determined using Sciex MacQuan software. Theplasma drug concentration of each sample was calculated by least-squareslinear regression analysis (nonweighted) of the peak area ratio(parent/internal standard) of the spiked plasma standards versusconcentration. The plasma concentration data were submitted tomultiexponential curve fitting using WinNonlin.3. The area under theplasma concentration-time curve was calculated using the lineartrapezoidal rule for the plasma concentration-time profiles.

In pharmacology, bioavailability (BA) is a subcategory of absorption andis used to describe the fraction of an administered dose of unchangeddrug that reaches the systemic circulation, one of the principalpharmacokinetic properties of drugs. By definition, when a medication isadministered intravenously, its bioavailability is 100% (Griffin, J. P.The Textbook of Pharmaceutical Medicine (6th Ed.) New Jersey: BMJBooks). However, when a medication is administered via other routes(such as orally), its bioavailability generally decreases (due toincomplete absorption and first-pass metabolism) and may vary frompatient to patient. Bioavailability is one of the essential tools inpharmacokinetics, as bioavailability must be considered when calculatingdosages for non-intravenous routes of administration. One way tocalculate bioavailability of a drug or agent is by dividing the plasmaconcentration following an oral dose by the concentration following anintravenous dose. The oral bioavailability (as represented by % F) inSprague-Dawley rats for representative compounds of the invention areprovided below in Table 3.

In the drug discovery setting, it is generally accepted that Lipinski's“rule of 5” predicts that poor oral absorption or poor permeation for adrug is likely when two or more of the following metrics are satisfied:i) there are more than 5 hydrogen bond donors, ii) the molecular weightis greater than 500, iii) there are greater than 10 hydrogen bondacceptors (expressed as the sum of nitrogen and oxygen atoms), or iv)the calculated Log P (c Log P) is greater than 5 (Lipinski et al. Adv.Drug Del. Rev. 2001, 3-26). Indeed, the combination of high molecularweight (>500) and high c Log P (>5) is the best predictor of poorabsorption or permeation. Compounds of the invention generally exceedthe recommended ranges pertaining to molecular weight (>500) and c Log P(>5). It is notable, therefore, that compounds of Formula (I) haveacceptable oral bioavailability in rats (as defined by % F>1 0, seeMartin J. Med. Chem. 2005, 48, 3164.), as illustrated in Table 3.

TABLE 3 PK Data, Rat p.o. Dose Molecular EXAMPLE weight g/mol cLogP F(%), dose 3 658.8 9.0 13, 5 mpk 7 674.8 6.4 21, 5 mpk 13 646.8 5.9 10, 5mpk 16 688.8 6.6 20, 5 mpk 17 735.9 8.3 13, 5 mpk 18 762.0 8.7 31, 5 mpk21 684.9 10.9 37, 5 mpk 23 682.3 9.5 17, 5 mpk 24 659.8 8.4 29, 5 mpk 42679.2 9.5 15, 1 mpk 43 672.9 9.8 20, 1 mpk 45 732.9 6.7 45, 1 mpk 46692.9 8.5 58, 1 mpk 49 641.8 8.3 15, 1 mpk 57 659.8 8.8 21, 1 mpk 58712.9 7.3 14, 1 mpk 59 680.8 6.4 31, 1 mpk

Data in Table 2 and cited Molt-4 data show the utility of compounds ofthe invention to functionally inhibit anti-apoptotic Bcl-xL protein in acellular context. The ability of compounds to kill FL5.12 cellsover-expressing Bcl-xL or human tumor cell lines that are dependant uponBcl-xL such as Molt-4 cells is a direct measure of the compound'sability to inhibit anti-apoptotic Bcl-xL protein function. Compounds ofthe invention are very effective in killing FL5.12 cells over-expressingBcl-xL or human tumor cell lines that are dependant upon Bcl-xL such asMolt-4 cells as demonstrated by low EC₅₀ values. In addition, asdemonstrated in Table 3, compounds of the invention have good oralbioavailability in preclinical rodent studies, and therefore may findutility as orally-dosed therapeutics in a clinical setting.

Overexpression of Bcl-xL proteins correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem. Cancers include, but are not limited to, hematologic and solidtumor types such as acoustic neuroma, acute leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia (monocytic,myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocyticand promyelocytic), acute t-cell leukemia, basal cell carcinoma, bileduct carcinoma, bladder cancer, brain cancer, breast cancer (includingestrogen-receptor positive breast cancer), bronchogenic carcinoma,Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordoma,choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronicmyelocytic (granulocytic) leukemia, chronic myelogenous leukemia, coloncancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, gastric carcinoma, germ cell testicular cancer,gestational trophobalstic disease, glioblastoma, head and neck cancer,heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer,hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lungcancer (including small cell lung cancer and non-small cell lungcancer), lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblasticleukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma,follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma),malignancies and hyperproliferative disorders of the bladder, breast,colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoidmalignancies of T-cell or B-cell origin, leukemia, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma,oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer,pancreatic cancer, papillary adenocarcinomas, papillary carcinoma,peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostatecancer (including hormone-insensitive (refractory) prostate cancer),rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma,sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small celllung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer,squamous cell carcinoma, synovioma, sweat gland carcinoma, testicularcancer (including germ cell testicular cancer), thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer,Wilms' tumor and the like.

It is also expected that compounds having Formula (I) would inhibitgrowth of cells expressing Bcl-xL proteins derived from a pediatriccancer or neoplasm including embryonal rhabdomyosarcoma, pediatric acutelymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatricalveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatricanaplastic large cell lymphoma, pediatric anaplastic medulloblastoma,pediatric atypical teratoid/rhabdoid tumor of the central nervoussystem, pediatric biphenotypic acute leukemia, pediatric Burkittslymphoma, pediatric cancers of Ewing's family of tumors such asprimitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm'stumor, pediatric favorable histology Wilm's tumor, pediatricglioblastoma, pediatric medulloblastoma, pediatric neuroblastoma,pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cellcancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoidkidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancerssuch as lymphoma and skin cancer and the like.

Autoimmune disorders include acquired immunodeficiency disease syndrome(AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia,inflammatory diseases, and thrombocytopenia, acute or chronic immunedisease associated with organ transplantation, Addison's disease,allergic diseases, alopecia, alopecia greata, atheromatousdisease/arteriosclerosis, atherosclerosis, arthritis (includingosteoarthritis, juvenile chronic arthritis, septic arthritis, Lymearthritis, psoriatic arthritis and reactive arthritis), autoimmunebullous disease, abetalipoprotemia, acquired immunodeficiency-relateddiseases, acute immune disease associated with organ transplantation,acquired acrocyanosis, acute and chronic parasitic or infectiousprocesses, acute pancreatitis, acute renal failure, acute rheumaticfever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats,adult (acute) respiratory distress syndrome, AIDS dementia complex,alcoholic cirrhosis, alcohol-induced liver injury, alcohol-inducedhepatitis, allergic conjunctivitis, allergic contact dermatitis,allergic rhinitis, allergy and asthma, allograft rejection,alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateralsclerosis, anemia, angina pectoris, ankylosing spondylitis associatedlung disease, anterior horn cell degeneration, antibody mediatedcytotoxicity, antiphospholipid syndrome, anti-receptor hypersensitivityreactions, aortic and peripheral aneurysms, aortic dissection, arterialhypertension, arteriosclerosis, arteriovenous fistula, arthropathy,asthenia, asthma, ataxia, atopic allergy, atrial fibrillation (sustainedor paroxysmal), atrial flutter, atrioventricular block, atrophicautoimmune hypothyroidism, autoimmune haemolytic anaemia, autoimmunehepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoidhepatitis), autoimmune mediated hypoglycaemia, autoimmune neutropaenia,autoimmune thrombocytopaenia, autoimmune thyroid disease, B celllymphoma, bone graft rejection, bone marrow transplant (BMT) rejection,bronchiolitis obliterans, bundle branch block, burns, cachexia, cardiacarrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy,cardiopulmonary bypass inflammation response, cartilage transplantrejection, cerebellar cortical degenerations, cerebellar disorders,chaotic or multifocal atrial tachycardia, chemotherapy associateddisorders, chlamydia, choleosatatis, chronic alcoholism, chronic activehepatitis, chronic fatigue syndrome, chronic immune disease associatedwith organ transplantation, chronic eosinophilic pneumonia, chronicinflammatory pathologies, chronic mucocutaneous candidiasis, chronicobstructive pulmonary disease (COPD), chronic salicylate intoxication,common varied immunodeficiency (common variable hypogammaglobulinaemia),conjunctivitis, connective tissue disease associated interstitial lungdisease, contact dermatitis, Coombs positive haemolytic anaemia, corpulmonale, Creutzfeldt-Jakob disease, cryptogenic autoimmune hepatitis,cryptogenic fibrosing alveolitis, culture negative sepsis, cysticfibrosis, cytokine therapy associated disorders, Crohn's disease,dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever,dermatitis, scleroderma, dermatologic conditions,dermatomyositis/polymyositis associated lung disease, diabetes, diabeticarteriosclerotic disease, diabetes mellitus, Diffuse Lewy body disease,dilated cardiomyopathy, dilated congestive cardiomyopathy, discoid lupuserythematosus, disorders of the basal ganglia, disseminatedintravascular coagulation, Down's Syndrome in middle age, drug-inducedinterstitial lung disease, drug-induced hepatitis, drug-induced movementdisorders induced by drugs which block CNS dopamine, receptors, drugsensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy,enteropathic synovitis, epiglottitis, Epstein-Barr virus infection,erythromelalgia, extrapyramidal and cerebellar disorders, familialhematophagocytic lymphohistiocytosis, fetal thymus implant rejection,Friedreich's ataxia, functional peripheral arterial disorders, femaleinfertility, fibrosis, fibrotic lung disease, fungal sepsis, gasgangrene, gastric ulcer, giant cell arteritis, glomerular nephritis,glomerulonephritides, Goodpasture's syndrome, goitrous autoimmunehypothyroidism (Hashimoto's disease), gouty arthritis, graft rejectionof any organ or tissue, graft versus host disease, gram negative sepsis,gram positive sepsis, granulomas due to intracellular organisms, group Bstreptococci (GBS) infection, Grave's disease, haemosiderosis associatedlung disease, hairy cell leukemia, hairy cell leukemia,Hallerrorden-Spatz disease, Hashimoto's thyroiditis, hay fever, hearttransplant rejection, hemachromatosis, hematopoietic malignancies(leukemia and lymphoma), hemolytic anemia, hemolytic uremicsyndrome/thrombolytic thrombocytopenic purpura, hemorrhage,Henoch-Schoenlein purpurea, Hepatitis A, Hepatitis B, Hepatitis C, HIVinfection/HIV neuropathy, Hodgkin's disease, hypoparathyroidism,Huntington's chorea, hyperkinetic movement disorders, hypersensitivityreactions, hypersensitivity pneumonitis, hyperthyroidism, hypokineticmovement disorders, hypothalamic-pituitary-adrenal axis evaluation,idiopathic Addison's disease, idiopathic leucopaenia, idiopathicpulmonary fibrosis, idiopathic thrombocytopaenia, idiosyncratic liverdisease, infantile spinal muscular atrophy, infectious diseases,inflammation of the aorta, inflammatory bowel disease, insulin dependentdiabetes mellitus, interstitial pneumonitis, iridocyclitis/uveitis/opticneuritis, ischemia-reperfusion injury, ischemic stroke, juvenilepernicious anaemia, juvenile rheumatoid arthritis, juvenile spinalmuscular atrophy, Kaposi's sarcoma, Kawasaki's disease, kidneytransplant rejection, legionella, leishmaniasis, leprosy, lesions of thecorticospinal system, linear IgA disease, lipidema, liver transplantrejection, Lyme disease, lymphederma, lymphocytic infiltrative lungdisease, malaria, male infertility idiopathic or NOS, malignanthistiocytosis, malignant melanoma, meningitis, meningococcemia,microscopic vasculitis of the kidneys, migraine headache, mitochondrialmultisystem disorder, mixed connective tissue disease, mixed connectivetissue disease associated lung disease, monoclonal gammopathy, multiplemyeloma, multiple systems degenerations (Mencel Dejerine-ThomasShi-Drager and Machado-Joseph), myalgic encephalitis/Royal Free Disease,myasthenia gravis, microscopic vasculitis of the kidneys, mycobacteriumavium intracellulare, mycobacterium tuberculosis, myelodyplasticsyndrome, myocardial infarction, myocardial ischemic disorders,nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis,nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic Imuscular atrophies, neutropenic fever, Non-alcoholic Steatohepatitis,occlusion of the abdominal aorta and its branches, occlusive arterialdisorders, organ transplant rejection, orchitis/epidydimitis,orchitis/vasectomy reversal procedures, organomegaly, osteoarthrosis,osteoporosis, ovarian failure, pancreas transplant rejection, parasiticdiseases, parathyroid transplant rejection, Parkinson's disease, pelvicinflammatory disease, pemphigus vulgaris, pemphigus foliaceus,pemphigoid, perennial rhinitis, pericardial disease, peripheralatherlosclerotic disease, peripheral vascular disorders, peritonitis,pernicious anemia, phacogenic uveitis, pneumocystis carinii pneumonia,pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,monoclonal gammopathy, and skin changes syndrome), post perfusionsyndrome, post pump syndrome, post-MI cardiotomy syndrome,postinfectious interstitial lung disease, premature ovarian failure,primary biliary cirrhosis, primary sclerosing hepatitis, primarymyxoedema, primary pulmonary hypertension, primary sclerosingcholangitis, primary vasculitis, Progressive supranucleo Palsy,psoriasis, psoriasis type 1, psoriasis type 2, psoriatic arthropathy,pulmonary hypertension secondary to connective tissue disease, pulmonarymanifestation of polyarteritis nodosa, post-inflammatory interstitiallung disease, radiation fibrosis, radiation therapy, Raynaud'sphenomenon and disease, Raynoud's disease, Refsum's disease, regularnarrow QRS tachycardia, Reiter's disease, renal disease NOS,renovascular hypertension, reperfusion injury, restrictivecardiomyopathy, rheumatoid arthritis associated interstitial lungdisease, rheumatoid spondylitis, sarcoidosis, Schmidt's syndrome,scleroderma, senile chorea, Senile Dementia of Lewy body type, sepsissyndrome, septic shock, seronegative arthropathies, shock, sickle cellanemia, Sjögren's disease associated lung disease, Sjörgren's syndrome,skin allograft rejection, skin changes syndrome, small bowel transplantrejection, sperm autoimmunity, multiple sclerosis (all subtypes), spinalataxia, spinocerebellar degenerations, spondyloarthopathy, sporadic,polyglandular deficiency type I, sporadic polyglandular deficiency typeII, Still's disease, streptococcal myositis, stroke, structural lesionsof the cerebellum, Subacute sclerosing panencephalitis, sympatheticophthalmia, Syncope, syphilis of the cardiovascular system, systemicanaphylaxis, systemic inflammatory response syndrome, systemic onsetjuvenile rheumatoid arthritis, systemic lupus erythematosus, systemiclupus erythematosus-associated lung disease, systemic sclerosis,systemic sclerosis-associated interstitial lung disease, T-cell or FABALL, Takayasu's disease/arteritis, Telangiectasia, Th2 Type and Th1 Typemediated diseases, thromboangitis obliterans, thrombocytopenia,thyroiditis, toxicity, toxic shock syndrome, transplants,trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibodyhepatitis), type B insulin resistance with acanthosis nigricans, typeIII hypersensitivity reactions, type IV hypersensitivity, ulcerativecolitic arthropathy, ulcerative colitis, unstable angina, uremia,urosepsis, urticaria, uveitis, valvular heart diseases, varicose veins,vasculitis, vasculitic diffuse lung disease, venous diseases, venousthrombosis, ventricular fibrillation, vitiligo acute liver disease,viral and fungal infections, vital encephalitis/aseptic meningitis,vital-associated hemaphagocytic syndrome, Wegener's granulomatosis,Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection ofany organ or tissue, yersinia and salmonella-associated arthropathy andthe like.

Schemes and Experimentals

The following abbreviations have the meanings indicated. ADDP means1,1′-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of(DHQD)₂PHAL, K₃Fe(CN)₆, K₂CO₃, and K₂SO₄; 9-BBN means9-borabicyclo(3.3.1)nonane; Boc means tert-butoxycarbonyl; (DHQD)₂PHALmeans hydroquinidine 1,4-phthalazinediyl diethyl ether; DBU means1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminumhydride; DIEA means diisopropylethylamine; DMAP meansN,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe means1,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppbmeans 1,4-bis(diphenylphosphino)-butane; dppe means1,2-bis(diphenylphosphino)ethane; dppf means1,1′-bis(diphenylphosphino)ferrocene; dppm means1,1-bis(diphenylphosphino)methane; EDAC.HCl means1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc meansfluorenylmethoxycarbonyl; HATU meansO-(7-azabenzotriazol-1-yl)-N,N′N′N′-tetramethyluroniumhexafluorophosphate; HMPA means hexamethylphosphoramide; IPA meansisopropyl alcohol; MP-BH₃ means macroporous triethylammoniummethylpolystyrene cyanoborohydride; TEA means triethylamine; TFA meanstrifluoroacetic acid; THF means tetrahydrofuran; NCS meansN-chlorosuccinimide; NMM means N-methylmorpholine; NMP meansN-methylpyrrolidine; PPh₃ means triphenylphosphine.

The following schemes are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. Compounds of this invention may bemade by synthetic chemical processes, examples of which are shownherein. It is meant to be understood that the order of the steps in theprocesses may be varied, that reagents, solvents and reaction conditionsmay be substituted for those specifically mentioned, and that vulnerablemoieties may be protected and deprotected, as necessary.

Schemes

As shown in Scheme 1, compounds of formula (1), wherein R¹, R², n, and mare as described herein, can be reacted with compounds of formula (2)wherein X is as described herein, in the presence of a carboxylactivating agent such as but not limited toN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, and acatalyst such but not limited to 4-dimethylaminopyridine, to providecompounds of formula (3). The reaction is typically performed at roomtemperature in a solvent such as but not limited to dichloromethane.Compounds of formula (4) can be prepared by reacting compounds offormula (3) with an acid such as but not limited to hydrochloric acid ina solvent such as but not limited to 1,4-dioxane. Compounds of formula(4) can be reacted with compounds of formula (5), wherein Z¹, R³ and pare as described herein and X³ is chloro or fluoro, in the presence of abase such as but not limited to cesium carbonate, to provide compoundsof formula (6). The reaction is typically performed at an elevatedtemperature in a solvent such as but not limited toN,N-dimethylacetamide. Compounds of formula (7) can be prepared byreacting compounds of formula (6) with4,4,5,5-tetramethyl-1,3,2-dioxaborolane in tetrahydrofuran, in thepresence of a base such as but not limited to triethylamine, and acatalyst such as but not limited to[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane. The reaction is typically performed at elevatedtemperature and with the addition of a solvent such as but not limitedto acetonitrile. Additionally, the reaction may be performed in amicrowave reactor.

After preparation as described in Scheme 1, compounds of formula (6) canbe reacted with a boronic acid (or the boronate equivalent) of formula(8) or an organotin or organozinc halide compound of formula (8a)wherein Y¹, L¹, and Y² are as described herein, and M is tributyltin ora zince halide, under Suzuki, Stille, or Negishi coupling conditionsknown to those skilled in the art and readily available in theliterature to provide compounds of formula (I). Alternatively, compoundsof formula (7), which can be prepared from compounds of formula (6) asdescribed in Scheme 1, can be reacted with compounds of formula (9)wherein X¹ is a triflate or halide, and Y¹, L¹, and Y² are as describedherein, under Suzuki coupling conditions known to those skilled in theart and readily available in the literature to provide compounds offormula (I).

As shown in Scheme 3, pyrazoles of formula (10), wherein R^(x1) ishydrogen or a substituent on Y¹ as described herein, can be reacted withalcohols of formula (11), wherein L¹ and Y² are as described herein, andcyanomethylenetributylphosphorane, to provide compounds of formula (12).The reaction is typically performed at ambient temperature in a solventsuch as but not limited to toluene. Compounds of formula (14) can beprepared by adding compounds of formula (13) wherein R^(x2) is anappropriate substituent as described herein for substituents on Y¹, andX² is a halide, to a cold solution of compounds of formula (12) treatedwith n-butyllithium in hexanes. The reaction is typically performed in asolvent such as but not limited to tetrahydrofuran. Compounds of formula(14) can be treated with N-bromosuccinimide or N-iodosuccinimide toprovide compounds of formula (15), wherein X⁴ is bromo or iodo. Thereaction is typically performed in a solvent such asN,N-dimethylformamide. Compounds of formula (15) can be reacted withcompounds of formula (7) under Suzuki coupling conditions known to thoseskilled in the art and readily available in the literature to providecompounds of formula (17), which are representative of compounds offormula (I). Alternatively, compounds of formula (15) can be reactedwith triisopropyl borate, in the presence of n-butyllithium in hexanes,followed by pinacol to provide compounds of formula (18). The additionsare typically performed at low temperature in a solvent such as but notlimited to tetrahydrofuran, toluene, or mixtures thereof. Alternatively,compounds of the formula (15) can be treated with4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the presence of a palladiumcatalyst system such as but not limited to bis(acetonitrile)palladiumdichloride and SPhos in a solvent such as but not limited to 1,4-dioxaneto provide compounds of the formula 18. The reaction is typicallyperformed at elevated temperature. Compounds of formula (18) can bereacted with compounds of formula (6) under Suzuki coupling conditionsknown to those skilled in the art and readily available in theliterature to provide compounds of formula (17), which arerepresentative of compounds of formula (I).

Pyrroles of formula (21) wherein R^(x1), R^(x2), and R^(x3) are hydrogenor are as described herein for substituents on Y¹, can be reacted withalcohols of formula (11), wherein Y² and L¹ are as described herein, andcyanomethylenetributylphosphorane, to provide compounds of formula (22).The reaction is typically performed at ambient temperature in a solventsuch as but not limited to toluene. Compounds of formula (22) can betreated with N-bromosuccinimide to provide compounds of formula (23).The reaction is typically performed in a solvent such asN,N-dimethylformamide. Compounds of formula (23) can be reacted withtriisopropyl borate, in the presence of n-butyllithium in hexanes,followed by pinacol to provide compounds of formula (24). The additionsare typically performed at low temperature in a solvent such as but notlimited to tetrahydrofuran, toluene, or mixtures thereof. Alternatively,compounds of the formula (23) can be treated with4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the presence of a palladiumcatalyst system such as but not limited to bis(acetonitrile)palladiumdichloride and SPhos in a solvent such as but not limited to 1,4-dioxaneto provide compounds of the formula (24). The reaction is typicallyperformed at an elevated temperature. Compounds of formula (24) can bereacted with compounds of formula (6) under Suzuki coupling conditionsknown to those skilled in the art and readily available in theliterature to provide compounds of formula (25), which arerepresentative of compounds of formula (I). Alternatively, compounds offormula (23) can be reacted with compounds of formula (7) under Suzukicoupling conditions known to those skilled in the art and readilyavailable in the literature to provide compounds of formula (25), whichare representative of compounds of formula (I).

Compounds of formula (22A), wherein Z is O, a substituted orunsubstituted N, or a substituted or unsubstituted C; R^(x1) is hydrogenor is as described herein for substituents on Y²; R^(x4) is alkyl; and nis 0, 1, or 2; can be added to a cooled solution of lithiumdiisopropylamide, followed by the addition of compounds of formula(23A); wherein R^(x2) is an appropriate substituent as described hereinfor substituents on Y¹, and X¹ is a halide; to provide compounds offormula (23B). The reaction is typically performed at low temperaturebefore warming to ambient temperature in a solvent such as but notlimited to tetrahydrofuran. Compounds of formula (23B) can be reactedwith LiAlH₄ to provide compounds of formula (24B). The reaction istypically performed at an elevated temperature in a solvent such as butnot limited to diethyl ether. Compounds of formula (25A) can be preparedby reacting compounds of formula (24B) with compounds of formula (24A)wherein Y¹ is as described herein; andcyanomethylenetributylphosphorane. The reaction is typically performedat ambient temperature in a solvent such as but not limited to toluene.Compounds of formula (25A) can be processed in a manner similar tocompounds of formula (12) in Scheme 3 and compounds of formula (22) inScheme 4 to provide compounds of formula (I).

As shown in Scheme 6, compounds of formula (27), wherein R^(x1) ishydrogen or a substituent on Y¹ as described herein, can be prepared byreacting compounds of formula (26) with trimethylsulfonium iodide, inthe presence of potassium tert-butoxide. The reaction is typicallyperformed at ambient temperature in an anhydrous solvent such as but notlimited to dimethylsulfoxide. Compounds of formula (27) can be added toa mixture of compounds of formula (24A) and a base such as but notlimited to cesium carbonate, to provide compounds of formula (28). Thereaction is typically performed at elevated temperature in a solventsuch as but not limited to N,N-dimethylformamide, and may be performedin a microwave reactor. Compounds of formula (28) can be treated withsodium hydride, followed by the addition of compounds of formula (13) toprovide compounds of formula (29). The reaction is typically performedat ambient temperature in a solvent such as but not limited totetrahydrofuran, and may involve the use of hexamethylphosphoramide.Compounds of formula (29) can be processed in a manner similar tocompounds of formula (12) in Scheme 3 and compounds of formula (22) inScheme 4 to provide compounds of formula (I).

Compounds of formula (33) wherein M is a boronic acid, boronate, ortributlytin attached to Y¹ and Y¹, L¹, and Y² are as described herein,and X³ is chloro or fluoro; can be reacted with compounds of formula(32) wherein Z¹, R³, and p are as described herein, under Suzuki orStille coupling conditions known to those skilled in the art and readilyavailable in the literature to provide compounds of formula (34).Compounds of formula (34) can be reacted with compounds of formula (4),in the presence of a base such as but not limited to cesium carbonate,to provide compounds of formula (I). The reaction is typically performedat an elevated temperature in a solvent such as but not limited toN,N-dimethylacetamide.

Triazoles of formula (36) can be prepared by reacting azides of formula(35), wherein L¹ and Y² are as described herein, with compounds offormula (36A) wherein R^(x2) is alkyl, under conditions known to thoseskilled in the art and readily available in the literature. Compounds offormula (37), wherein Z¹ is as described herein, can be reacted withcompounds of formula (36) under Stille coupling conditions known tothose skilled in the art and readily available in the literature toprovide compounds of formula (38). Compounds of formula (4), wherein R¹,R², X, m and n are as described herein, can be reacted with compounds offormula (38), in the presence of a base such as but not limited tocesium carbonate, to provide compounds of formula (39), which arerepresentative of compounds of formula (I). The reaction is typicallyperformed at an elevated temperature in a solvent such as but notlimited to N,N-dimethylacetamide.

As shown in Scheme 9,1-bromo-3-(bromomethyl)-adamantane can be reactedwith compounds of formula (30), wherein Y¹ is as described herein, inthe presence of sodium hydride to provide compounds of formula (31). Theaddition is typically performed in a solvent such as but not limited toN,N-dimethylformamide at low temperature, prior to warming to anelevated temperature. Compounds of formula (31) can be reacted withcompounds of formula (32), optionally in the presence of silver sulfate,wherein R⁸ is as described herein and Z² is O, NH, or NR⁸, to providecompounds of formula (33) which are representative of compounds offormula (9). The reaction is typically performed at elevated temperatureand may involve an additional solvent. Additionally, the reaction may beperformed in a microwave reactor. Compounds of formula (33) can beprocessed in a manner similar to compounds of formula (12) in Scheme 3and compounds of formula (22) in Scheme 4 to provide compounds offormula (I).

The following examples are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. The exemplified compounds werenamed using ACD/ChemSketch Version 5.06 (5 Jun. 2001, Advanced ChemistryDevelopment Inc., Toronto, Ontario), ACD/ChemSketch Version 12.01 (13May 2009), Advanced Chemistry Development Inc., Toronto, Ontario), orChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.). Intermediateswere named using ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.).

EXAMPLES Example 16-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 1A4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazole

A mixture of 1-(bromomethyl)adamantane (0.458 g) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.377 g) inN,N-dimethylformamide (5 mL) was cooled to 0° C. To this solution wasadded 60% sodium hydride (0.096 g). The solution was heated at 70° C.overnight. The reaction mixture was partitioned between water and ethylacetate. The aqueous layer was extracted with additional ethyl acetatetwice. The combined organic layers were washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was purified by flashcolumn chromatography on silica gel eluting with 25% ethyl acetate inhexanes to provide the title compound.

Example 1B tert-butyl8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid(6.8 g) and benzo[d]thiazol-2-amine (5.52 g) in dichloromethane (80 mL)was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride(9.4 g) and 4-dimethylaminopyridine (6 g). The mixture was stirred atroom temperature overnight. The reaction mixture was diluted withdichloromethane (400 mL), washed with 5% aqueous HCl, water, and brine,and dried over Na₂SO₄. The mixture was filtered and the filtrate wasconcentrated under reduced pressure to provide the title compound.

Example 1CN-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamidedihydrochloride

To a solution of EXAMPLE 1B (8.5 g) in dichloromethane (80 mL) was added2N HCl in ether (80 mL). The reaction mixture was stirred at roomtemperature overnight and concentrated under reduced pressure to providethe title compound.

Example 1D tert-butyl 3-bromo-6-chloropicolinate

Tosyl chloride (7.7 g) was added to a solution of 2-chloro-5-bromopicolinic acid (4 g) and pyridine (9.2 mL) in t-butanol (33 mL) at 0° C.The reaction was then stirred at room temperature for 12 hours. NaHCO₃(aqueous, saturated) was then added and the mixture was extracted threetimes with ethyl acetate. The combined organic phases were washed withbrine and dried over Na₂SO₄. Filtration and evaporation of the organicsolvent provided the title compound which was used in the next stepwithout further purification.

Example 1E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-bromopicolinate

EXAMPLE 1D (0.736 g), EXAMPLE 1C (1.62 g), and Cs₂CO₃ (4.1 g) werestirred in 12 mL of anhydrous N,N-dimethylacetamide at 120° C. for 12hours. The cooled reaction mixture was then diluted with ethyl acetateand 10% citric acid. The organic phase was washed three times withcitric acid, once with water and brine, and dried over Na₂SO₄.Filtration and concentration afforded crude material, which waschromatographed on silica gel using 0-40% ethyl acetate in hexanes toprovide the title compound.

Example 1F tert-butyl3-{1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}-6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylate

A mixture of EXAMPLE 1E (0.100 g), EXAMPLE 1A (0.059 g),tetrakis(triphenylphosphine)palladium(0) (0.022 g) and CsF (0.090 g) in1,2-dimethoxyethane (2 mL) and methanol (1 mL) was heated at 120° C. for30 minutes under microwave heating conditions (Biotage Initiator). Thereaction mixture was partitioned between water and ethyl acetate. Theaqueous layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by flash columnchromatography on silica gel eluting with 25% ethyl acetate in hexanesto afford the title compound.

Example 1G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

EXAMPLE 1F (90 mg) in dichloromethane (3 mL) was treated withtrifluoroacetic acid (3 mL), and the reaction was stirred at roomtemperature for 24 hours. The volatiles were removed under reducedpressure. The residue was purified by Prep HPLC using Gilson systemeluting with 20-80% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid. The desired fractions were combined andfreeze-dried to provide the title compound. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.80 (d, 1H),7.82 (d, 1H), 7.67 (s, 1H), 7.61 (d, 1H), 7.43 (s, 1H), 7.46-7.50 (m,1H), 7.42-7.44 (m, 1H), 7.34-7.38 (m, 2H), 6.94 (d, 1H), 4.94 (s, 2H),3.85-3.88 (m, 2H), 3.77 (s, 2H), 3.00 (t, 2H), 1.92 (m, 3H), 1.52-1.65(m, 6H), 1.45-1.46 (m, 6H).

Example 26-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3,5-dimethyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 2A3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazole

To a solution of 1-adamantanemethanol (0.090 g),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.160 g) and cyanomethylenetributylphosphorane (0.215 g) were added andstirred together in toluene (2 mL) at room temperature. After stirringovernight the reaction was loaded directly onto silica gel and elutedusing a gradient of 2% to 20% ethyl acetate/hexanes to provide the titlecompound.

Example 2B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3,5-dimethyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

EXAMPLE 1E (0.150 g), EXAMPLE 2A (0.121 g),tetrakis(triphenylphosphine)palladium(0) (14 mg) and cesium carbonate(0.260 g) were stirred together in N,N-dimethylformamide (1 mL), dioxane(0.7 mL), and water (0.4 mL) and the reaction degassed with nitrogen andheated at 100° C. for 1 hour. The reaction was diluted with ethylacetate (25 mL) and washed with water (25 mL) and brine (25 mL), driedover magnesium sulfate, filtered, and concentrated. Silica gelchromatography eluting with a gradient of 2% to 50% ethylacetate/hexanes provided the title compound.

Example 2C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3,5-dimethyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

To EXAMPLE 2B (0.070 g) in dichloromethane (1 mL) was added TFA (1 mL)and the reaction was stirred overnight. The reaction was concentrated,dissolved in dichloromethane and loaded onto silica gel and eluted usinga gradient of 0.5% to 5% methanol/dichloromethane to provide the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 13.04 (s, 1H), 12.84(s, 1H), 8.04 (dd, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.62 (t, 2H),7.54-7.32 (m, 5H), 7.22-7.14 (m, 2H), 7.11-7.01 (m, 2H), 6.93 (d, 1H),4.94 (s, 2H), 4.30 (t, 2H), 3.86 (t, 2H), 3.08 (t, 2H), 3.00 (t, 2H).

Example 36-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 3A 1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazole

The title compound was prepared by substituting pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 3B1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-5-methyl-1H-pyrazole

A solution of EXAMPLE 3A (869 mg) in tetrahydrofuran (10 mL) was chilledto −45° C. n-Butyllithium (2.3 M solution in hexanes, 2.10 mL) was addeddropwise over 5 minutes. The reaction was stirred for 1.5 hours, duringwhich time the temperature increased to −20° C. Iodomethane (0.305 mL)was added dropwise over 3 minutes. The reaction was stirred for 30minutes between −20 and −15° C. Water (25 mL) was added and the mixturewas extracted with ethyl acetate (3×25 mL). The extracts were dried(Na₂SO₄), filtered, and concentrated to provide the title compound.

Example 3C1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-4-bromo-5-methyl-1H-pyrazole

EXAMPLE 3B (865 mg) was dissolved in N,N-dimethylformamide (7 mL) andN-bromosuccinimide (334 mg) was added. The reaction was stirred at roomtemperature for 1 hour. Water (25 mL) was added and the product wasobtained by filtration.

Example 3D1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

EXAMPLE 3C (250 mg) was placed into a flask, and was degassed with N₂.Tetrahydrofuran (2.5 mL) and toluene (2.500 mL) were added and thesolution was chilled to −78° C. Triisopropyl borate (0.243 mL) wasadded, followed by dropwise addition of n-butyllithium (2.3 M inhexanes, 0.6 mL) over 5 minutes. The mixture was stirred for 15 minutesat −78° C. and then a degassed solution of pinacol (143 mg) intetrahydrofuran (1 mL) was added over 2 minutes. After stirring for 10minutes at −78° C., the reaction was warmed to room temperature andstirred for 45 minutes. Water (0.073 mL) was then added and the mixturewas stirred for 2 hours. The crude reaction mixture was concentrated todryness to provide the title compound.

Example 3E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-[1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-5-methyl-1H-pyrazol-4-yl]picolinate

The title compound was prepared by substituting EXAMPLE 3D for EXAMPLE2A in EXAMPLE 2B.

Example 3F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 3E for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 12.74 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.40-7.53(m, 3H), 7.31-7.39 (m, 2H), 7.26 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H),3.89 (t, 2H), 3.70 (s, 2H), 3.01 (t, 2H), 2.10 (s, 3H), 1.89-1.95 (m,3H), 1.48-1.69 (m, 12H).

Example 46-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(spiro[3.5]non-7-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 4A 4-bromo-1-(spiro[3.5]nonan-7-ylmethyl)-1H-pyrazole

The title compound was prepared by substituting 4-bromo-1H-pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand 7-hydroxymethyl-spiro[3.5]nonane for 1-adamantanemethanol in EXAMPLE2A.

Example 4B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate

A mixture of EXAMPLE 1E (1.2 g), 1.0 M4,4,5,5-tetramethyl-1,3,2-dioxaborolane in tetrahydrofuran (4.24 mL),triethylamine (0.92 mL), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (0.087 g) in CH₃CN (15 mL) was heated at 100° C. undermicrowave conditions (Biotage) for 30 minutes. After cooling, thereaction mixture was partitioned between water and ethyl acetate. Theorganic layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by flash columnchromatography on silica gel to provide the title compound.

Example 4C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(spiro[3.5]nonan-7-ylmethyl)-1H-pyrazol-4-yl)picolinate

A suspension of EXAMPLE 4B (50 mg), EXAMPLE 4A (23.12 mg),tris(dibenzylideneacetone)dipalladium(0) (7 mg),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (12 mg)and potassium phosphate (52.0 mg) in tetrahydrofuran (1.5 mL) and water(0.5 mL) was heated under microwave conditions (Biotage) at 140° C. for5 minutes. The reaction mixture was diluted with ethyl acetate,separated, and purified by chromatography on silica gel using 10-60%ethyl acetate/hexanes as eluent to provide the title compound.

Example 4D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(spiro[3.5]non-7-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 4C for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.74 (s, 1H), 7.69 (d, 1H), 7.61 (d,1H), 7.52 (s, 1H), 7.45-7.51 (m, 1H), 7.40-7.44 (m, 1H), 7.36 (t, 2H),6.94 (d, 1H), 4.94 (s, 2H), 3.83-3.93 (m, 3H), 3.00 (t, 2H), 1.73-1.85(m, 2H), 1.55-1.75 (m, 8H), 1.35 (d, 2H), 1.09-1.23 (m, 2H), 0.88-1.04(m, 2H).

Example 56-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 5A4-bromo-1-{[3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazole

The title compound was prepared by substituting 4-bromo-1H-pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand 3,5-dimethyl-1-adamantanemethanol for 1-adamantanemethanol inEXAMPLE 2A.

Example 5B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 5A for EXAMPLE4A in EXAMPLE 4C.

Example 5C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 5B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.67 (s, 1H), 7.61 (d,1H), 7.53 (s, 1H), 7.44-7.51 (m, 1H), 7.40-7.45 (m, 1H), 7.36 (t, 2H),6.94 (d, 1H), 4.94 (s, 2H), 3.87 (t, 2H), 3.80 (s, 2H), 3.00 (t, 2H),1.96-2.05 (m, 1H), 1.26 (d, 6H), 0.96-1.17 (m, 6H), 0.77 (s, 6H).

Example 66-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-hydroxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 6A3-[(4-bromo-1H-pyrazol-1-yl)methyl]tricyclo[3.3.1.1^(3,7)]decan-1-ol

The title compound was prepared by substituting 4-bromo-1H-pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand 3-hydroxy-1-adamantanemethanol for 1-adamantylmethanol in EXAMPLE2A.

Example 6B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-hydroxytricyclo[3.3.1.1^(3,7)dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 6A for EXAMPLE4A in EXAMPLE 4C.

Example 6C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-hydroxytricyclo[3.3.1.1^(3,7)dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 6B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 13.06 (s,1H), 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.68 (s,1H), 7.61 (d, 1H), 7.53 (s, 1H), 7.44-7.51 (m, 1H), 7.40-7.44 (m, 1H),7.35 (t, 2H), 6.93 (d, 1H), 4.94 (s, 2H), 4.35 (s, 1H), 3.87 (t, 2H),3.82 (s, 2H), 3.00 (t, 2H), 2.08 (s, 2H), 1.36-1.56 (m, 6H), 1.33 (s,6H).

Example 76-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 7A1-[(3-bromotricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-4-iodo-1H-pyrazole

A mixture of 1-bromo-3-(bromomethyl)-adamantane (1.0 g) and4-iodopyrazole (0.63 g) in N,N-dimethylformamide (10 mL) was cooled to0° C. To this solution was added 60% sodium hydride (0.20 g). Thesolution was stirred at 65° C. overnight. The reaction mixture waspartitioned between water and ethyl acetate. The aqueous layer wasextracted with additional ethyl acetate twice. The combined organiclayers were washed three times with water, washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was purified by flashcolumn chromatography on silica gel eluting with 10% ethyl acetate inhexanes to provide the title compound.

Example 7B4-iodo-1-[(3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrazole

EXAMPLE 7A (5 g), silver sulfate (6 g) and methanol (15 mL) were heatedat 110° C. under microwave conditions (Biotage, Initiator) for 60minutes. After cooling to room temperature, the suspension was filtered.The solid residue was washed by ethyl acetate (3×5 mL) and filtered. Thecombined solution was dried under vacuum. The residue was taken up intodichloromethane and purified by flash chromatography (Varian, SuperflashSF40-200 g column), eluting with 0-70% ethyl acetate/hexane, to providethe title compound.

Example 7C tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 7B for EXAMPLE4A in EXAMPLE 4C.

Example 7D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 7C for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.71 (m, 2H), 7.61 (d, 1H), 7.54 (s,1H), 7.41 (m, 4H), 6.94 (d, 1H), 4.94 (s, 2H), 3.87 (m, 4H), 3.07 (s,3H), 3.00 (t, 2H), 2.14 (m, 2H), 1.46 (m, 12H).

Example 86-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(2-methoxyethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 8A4-iodo-1-{[3-(2-methoxyethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazole

The title compound was prepared by substituting 2-methoxyethanol formethanol in EXAMPLE 7B.

Example 8B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(2-methoxyethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 8A for EXAMPLE4A in EXAMPLE 4C.

Example 8C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(2-methoxyethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 8B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (s, 1H), 7.79 (s, 1H), 7.70 (m, 2H), 7.61 (d, 1H), 7.54 (s,1H), 7.40 (m, 5H), 6.94 (d, 1H), 4.94 (s, 2H), 3.86 (m, 4H), 3.42 (m,2H), 3.35 (m, 2H), 3.21 (s, 3H), 3.00 (t, 2H), 2.13 (m, 2H), 1.46 (m,12H).

Example 96-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5,7-trimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 9A 3,5,8-trimethyl-1-adamantanemethanol

To a solution of 3,5,8-trimethyl-1-adamantane carboxylic acid (0.5 g) intetrahydrofuran (3 mL) was dropwise added BH₃.tetrahydrofuran (4.50 mL)and the mixture was stirred at room temperature for 14 hours. Thereaction mixture was quenched with methanol (3 mL), concentrated andpurified by chromatography on silica gel using 0-30% ethylacetate/hexanes as eluent to provide the title compound.

Example 9B4-iodo-1-{[3,5,7-trimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 9A for1-adamantanemethanol and 4-iodopyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 9C tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5,7-trimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrazol-4-yl}picolinate

The title compound was prepared by substituting EXAMPLE 9B for EXAMPLE4A in EXAMPLE 4C.

Example 9D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5,7-trimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 9C for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.67 (s, 1H), 7.61 (d,1H), 7.53 (s, 1H), 7.48 (t, 1H), 7.40-7.44 (m, 1H), 7.36 (t, 2H), 6.95(d, 1H), 3.87 (t, 1H), 3.82 (s, 2H), 3.00 (t, 2H), 1.03 (s, 6H),0.92-1.01 (m, 6H), 0.78 (s, 9H).

Example 106-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 10A 2-adamantanemethanol

The title compound was prepared by substituting 2-adamantane carboxylicacid for 3,5,8-trimethyl-1-adamantane carboxylic acid in EXAMPLE 9A.

Example 10B 1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-4-iodo-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 10A for1-adamantanemethanol and 4-iodopyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 10C tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 10B for EXAMPLE4A in EXAMPLE 4C.

Example 10D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 10C for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 8.04 (d, 1H), 7.74-7.84 (m, 2H), 7.69 (d, 1H), 7.61 (d, 1H), 7.52(s, 1H), 7.40-7.51 (m, 2H), 7.36 (t, 2H), 6.94 (d, 1H), 4.94 (s, 2H),4.21 (d, 2H), 3.86 (t, 2H), 3.17 (s, 2H), 3.00 (t, 2H), 2.13-2.24 (m,1H), 1.98 (d, 2H), 1.44-1.89 (m, 12H), 1.07 (s, 1H).

Example 116-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-bromotricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 11A tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-bromotricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 7A for EXAMPLE4A in EXAMPLE 4C.

Example 11B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-bromotricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 11A for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.71 (d, 2H), 7.61 (d, 1H), 7.56 (s,1H), 7.45 (m, 2H), 7.35 (m, 2H), 6.95 (d, 1H), 4.94 (s, 2H), 3.87 (m,4H), 3.00 (t, 2H), 2.25 (m, 2H), 2.12 (m, 6H), 1.54 (m, 6H).

Example 126-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(propan-2-yloxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 12A4-iodo-1-{[3-(propan-2-yloxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazole

The title compound was prepared by substituting propan-2-ol for methanolin EXAMPLE 7B.

Example 12B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(propan-2-yloxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 12A for EXAMPLE4A in EXAMPLE 4C.

Example 12C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(propan-2-yloxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 12B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.70 (m, 2H), 7.61 (d, 1H), 7.53 (s,1H), 7.41 (m, 4H), 6.94 (d, 2H), 4.94 (s, 2H), 3.86 (m, 4H), 3.00 (t,2H), 2.11 (m, 2H), 1.62 (m, 2H), 1.49 (m, 3H), 1.37 (m, 7H), 0.98 (d,6H).

Example 136-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 13A 2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethanol

To a solution of (oxatricyclo[3.3.1.1^(3,7)]dec-1-yl)-2-carboxylic acid(0.32 g) in diethyl ether (5 mL) was added lithium aluminum hydride(1.0M in tetrahydrofuran, 2.1 mL) at 0° C. The reaction was allowed towarm to room temperature and was stirred for 2 hours. The reaction wascooled to 0° C. and quenched with water (0.24 mL). 15% Aqueous NaOH(0.24 mL) was added followed by more water (0.72 mL). The reaction wasstirred for 1 hour, and magnesium sulfate was added. The mixture wasfiltered and concentrated to provide the title compound.

Example 13B1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 13A for1-adamantanemethanol and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 13C tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 13B for EXAMPLE2A in EXAMPLE 2B.

Example 13D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 13C for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.72 (t, 2H), 7.61 (d, 1H), 7.52 (s,1H), 7.42 (m, 4H), 6.94 (d, 1H), 4.94 (s, 2H), 3.99 (s, 1H), 3.94 (s,2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.07 (s, 2H), 1.74 (m, 4H), 1.55 (m,6H).

Example 146-[8-(1,3-benzothiazol-2-ylcarbamoyl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 14A methyl2-(5-bromo-6-(tert-butoxycarbonyl)pyridin-2-yl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-8-carboxylate

Methyl 4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-8-carboxylate (500mg), EXAMPLE 1D (572 mg), and triethylamine (0.545 mL) in anhydrousdimethylsulfoxide (6.5 mL) was heated to 100° C. overnight, and themixture was then cooled to room temperature. The reaction was quenchedby the addition of saturated aqueous sodium bicarbonate solution (15 mL)and ethyl acetate (15 mL). The layers were separated, and the aqueouslayer was extracted with additional ethyl acetate (2×15 mL). Thecombined organics were dried with anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel with 0-40% ethyl acetate/hexanes to providethe title product.

Example 14B2-(5-bromo-6-(tert-butoxycarbonyl)pyridin-2-yl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-8-carboxylicacid

To an ambient solution of EXAMPLE 14A (245 mg) in tetrahydrofuran (2.1mL) was added a solution of LiOH (30.9 mg) in water (0.52 mL). Thereaction was stirred overnight, diluted with 2 mL water and 2 mL ethylacetate, and acidified to pH˜3 with 10% aqueous HCl solution. The layerswere separated, and the aqueous layer was extracted with additionalethyl acetate (2×8 mL). The combined organic layers were dried withanhydrous sodium sulfate, filtered and concentrated under reducedpressure to provide the title compound.

Example 14C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-bromopicolinate

An ambient solution of EXAMPLE 14B (182 mg), benzo[d]thiazol-2-amine(71.1 mg), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimidehydrochloride (113 mg), 1-hydroxybenzotriazole hydrate (91 mg), andN-methylmorpholine (0.065 mL) was stirred overnight. An additional 1equivalent each of 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimidehydrochloride, N-methylmorpholine, 1-hydroxybenzotriazole hydrate, and2-aminobenzothiazole were added, and the reaction was heated to 40° C.for 4 hours. The reaction mixture was cooled to room temperature andquenched by the addition of saturated aqueous bicarbonate solution andethyl acetate. The layers were separated, and the aqueous was extractedwith additional 2× ethyl acetate. The combined organics were dried withanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by chromatography on silica gel with0-50% ethyl acetate/hexanes to provide the title product.

Example 14D tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]picolinate

A mixture of EXAMPLE 14C (70 mg), EXAMPLE 3D (63 mg), K₃PO₄ (87 mg),Pd₂(dba)₃ (2.7 mg), and1,3,5,7-tetramethyl-6-tetradecyl-2,4,8-trioxa-6-phosphaadamantane (4.9mg) in a reaction vial equipped with a magnetic stir bar was degassedwith nitrogen. In a separate vial a 1:1 mixture of 1,4-dioxane and water(0.2 M total concentration) was degassed by a stream of nitrogen for 20min. The solvent was transferred by syringe to the reaction vialcontaining the solid reactants. The reaction was heated to 90° C. for 4hours. The reaction was quenched by the addition of saturated aqueousbicarbonate solution (5 mL) and ethyl acetate (5 mL). The layers wereseparated, and the aqueous was extracted with additional ethyl acetate(2×5 mL). The combined organics were dried with anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by chromatography on silica gel (12 g) with 0-50% ethylacetate/hexanes to provide the title product.

Example 14E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 14D for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.82 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.69 (d, 1H), 7.58 (d, 1H), 7.42 (m,5H), 7.27 (s, 1H), 7.00 (d, 1H), 4.93 (s, 2H), 3.71 (s, 2H), 2.11 (s,2H), 1.93 (s, 3H), 1.60 (m, 15H), 1.34 (s, 6H).

Example 156-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(morpholin-4-yl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 15A4-{3-[(4-iodo-1H-pyrazol-1-yl)methyl]tricyclo[3.3.1.1^(3,7)]dec-1-yl}morpholine

The title compound was prepared by substituting morpholine for methanolin EXAMPLE 7B.

Example 15B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(morpholin-4-yl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 15A for EXAMPLE4A in EXAMPLE 4C.

Example 15C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(morpholin-4-yl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 15B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 9.15 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.71 (m, 2H), 7.62 (d,1H), 7.57 (s, 1H), 7.41 (m, 4H), 6.96 (d, 1H), 4.95 (s, 2H), 3.94 (m,6H), 3.40 (m, 2H), 3.05 (m, 4H), 2.25 (m, 4H), 1.86 (m, 2H), 1.70 (m,4H), 1.38 (m, 6H).

Example 166-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 16A (3-bromotricyclo[3.3.1.1^(3,7)]dec-1-yl)methanol

In a 250 ml round-bottomed flask, 3-bromoadamantane-1-carboxylic acid(7.89 g) was dissolved in tetrahydrofuran (30 mL). Boranetetrahydrofuran complex (1M in hexane, 60 mL) was added slowly. Themixture was stirred at room temperature overnight. Methanol (20 mL) wasadded to the solution slowly. After removal of the solvents, methanol (5mL) was added to the oily residue. Removal of the solvent provided thetitle compound.

Example 16B1-[(3-bromotricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 16A for1-adamantanemethanol and pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 16C1-[(3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 16B for EXAMPLE7A in EXAMPLE 7B.

Example 16D1-[(3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 16C for EXAMPLE3A in EXAMPLE 3B.

Example 16E4-iodo-1-[(3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-5-methyl-1H-pyrazole

A mixture of EXAMPLE 16D (0.116 g) and N-iodosuccinimide (0.11 g) in 1mL DMF was stirred overnight. The mixture was taken up in ethyl acetate,and the resulting solution was washed three times with water, and brine,then dried with anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by chromatography onsilica gel with 0-50% ethyl acetate/hexanes to provide the titlecompound.

Example 16F tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 16E for EXAMPLE4A in EXAMPLE 4C.

Example 16G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxytricyclo[3.3.1.1³7]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid

The title compound was prepared by substituting EXAMPLE 16F for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.42 (m, 5H), 7.27 (s,1H), 6.94 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.79 (s, 2H), 3.08 (s,3H), 3.01 (t, 2H), 2.12 (m, 5H), 1.49 (m, 12H).

Example 17N-(1,3-benzothiazol-2-yl)-2-{6-[(methylsulfonyl)carbamoyl]-5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

EXAMPLE 3F (220 mg), methanesulfonamide (40 mg),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (100 mg),and 4-(dimethylamino)pyridine (80 mg) were dissolved in dichloromethane(2.5 mL) and stirred at room temperature over the weekend. The reactionmixture was concentrated and purified by Prep HPLC using Gilson systemeluting with 20-80% acetonitrile in 0.1% water. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ ppm 12.84 (br s, 1H), 11.83 (s, 1H), 8.01 (d,1H), 7.77 (d, 1H), 7.61 (d, 1H), 7.52 (d, 1H), 7.44 (m, 2H), 7.36 (m,2H), 7.26 (s, 1H), 6.96 (d, 1H), 4.95 (s, 2H), 3.92 (t, 2H), 3.69 (s,2H), 3.10 (s, 3H), 3.02 (t, 2H), 2.10 (s, 3H), 1.90 (br s, 3H), 1.61 (brm, 3H), 1.50 (br m, 9H).

Example 18N-(1,3-benzothiazol-2-yl)-2-{6-[(cyclopropylsulfonyl)carbamoyl]-5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

The title compound was prepared by substituting cyclopropanesulfonamidefor methanesulfonamide in EXAMPLE 17. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ ppm 12.85 (br s, 1H), 11.74 (s, 1H), 8.02 (d,1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.53 (d, 1H), 7.46 (m, 2H), 7.36 (m,2H), 7.28 (s, 1H), 7.00 (d, 1H), 4.98 (s, 2H), 3.92 (t, 2H), 3.70 (s,2H), 3.02 (t, 2H), 2.77 (m, 1H), 2.11 (s, 3H), 1.91 (br s, 3H), 1.62 (brm, 3H), 1.51 (br m, 9H), 1.00 (m, 2H), 0.90 (m, 2H).

Example 19N-(1,3-benzothiazol-2-yl)-2-{5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-(2H-tetrazol-5-yl)pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamideExample 19AN-(benzo[d]thiazol-2-yl)-2-(5-bromo-6-cyanopyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

The title compound was prepared by substituting3-bromo-6-chloropicolinonitrile for EXAMPLE 1D in EXAMPLE 1E.

Example 19BN-(1,3-benzothiazol-2-yl)-2-{5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[(cyano)-pyridin-2-yl]-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

A mixture of EXAMPLE 19A (0.245 g), EXAMPLE 3D (0.220 g),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.021 g),potassium phosphate (0.375 g) andtris(dibenzylideneacetone)dipalladium(0) (0.011 g) were added to dioxane(1.3 mL) and water (1.3 mL). The reaction was degassed with nitrogen,sealed and heated to 90° C. After 2 hours the reaction was cooled,diluted with chloroform (40 mL) and washed with brine (30 mL). Thereaction was dried over sodium sulfate, filtered, and concentrated.Silica gel chromatography eluting with a gradient of 5% to 45% ethylacetate/hexanes over 30 minutes provided the title compound.

Example 19CN-(1,3-benzothiazol-2-yl)-2-{5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-(2H-tetrazol-5-yl)pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

EXAMPLE 19B (100 mg) was dissolved in N,N-dimethylformamide (1.5 mL),and sodium azide (96 mg) and triethylamine hydrochloride (196 mg) wereadded. The reaction was heated at 110° C. overnight. The reactionmixture was cooled, filtered, and purified by Prep HPLC using Gilsonsystem eluting with 20-80% acetonitrile in water containing 0.1%trifluoroacetic acid. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.84(br s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (m, 2H), 7.46 (m, 2H), 7.36(m, 2H), 7.20 (s, 1H), 7.05 (d, 1H), 4.99 (s, 2H), 4.01 (t, 2H), 3.67(s, 2H), 3.03 (t, 2H), 1.92 (br s, 3H), 1.83 (s, 3H), 1.60 (br m, 6H),1.48 (br m, 6H).

Example 206-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-4-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylicacid Example 20A1-[(4-bromo-3-methylphenoxy)methyl]tricyclo[3.3.1.1^(3,7)]decane

The title compound was prepared by substituting 4-bromo-3-methylphenolfor3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 20B3-{2-methyl-4-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}-6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid tert-butyl ester

EXAMPLE 4B (120 mg), EXAMPLE 20A (90 mg),trans-dichlorobis(triphenylphosphine)palladium (II) (30 mg), and cesiumcarbonate (280 mg) were added to a microwave vial. N,N-dimethylformamide(1.0 mL), 1,4-dioxane (0.7 mL), and water (0.4 mL) were added. The vialwas placed in a microwave reactor and subjected to 120° C. for 15minutes. The solution was then added to water and extracted with 30%ethyl acetate in hexanes. The extract was washed with brine and driedover anhydrous sodium sulfate. The solution was filtered, concentratedand purified on silica gel using 30% ethyl acetate in hexanes.

Example 20C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-4-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 20B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51-7.31 (m, 5H),6.95 (d, 1H), 6.91 (d, 1H), 6.79 (d, 1H), 6.70 (dd, 1H), 4.97 (s, 2H),3.91 (t, 2H), 3.51 (s, 2H), 3.03 (t, 2H), 2.02 (s, 3H), 1.98 (bs, 3H),1.78-1.58 (m, 12H).

Example 216-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylicacid Example 21A1-[(3-bromo-2-methylphenoxy)methyl]tricyclo[3.3.1.1^(3,7)]decane

The title compound was prepared by substituting 3-bromo-2-methylphenolfor3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 21B3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}-6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 21A for EXAMPLE20A in EXAMPLE 20B.

Example 21C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 21B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51-7.31 (m, 5H),7.08 (t, 1H), 6.98 (d, 1H), 6.84 (d, 1H), 6.62 (d, 1H), 4.98 (s, 2H),3.92 (t, 2H), 3.52 (s, 2H), 3.03 (t, 2H), 1.99 (s, 3H), 1.92 (bs, 3H),1.78-1.59 (m, 12H).

Example 226-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylicacid Example 22A 1-[(3-bromophenoxy)methyl]tricyclo[3.3.1.1^(3,7)]decane

The title compound was prepared by substituting 3-bromophenol for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 22B3-{3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}-6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 22A for EXAMPLE20A in EXAMPLE 20B.

Example 22C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 22B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(bs, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.67 (d, 1H), 7.62 (d, 1H),7.50-7.43 (m, 2H), 7.39-7.33 (m, 2H), 7.29-7.23 (m, 1H), 6.97 (d, 1H),6.90-6.83 (m, 3H), 4.98 (s, 2H), 3.90 (t, 2H), 3.52 (s, 2H), 3.02 (t,2H), 1.98 (bs, 3H), 1.78-1.59 (m, 12H).

Example 236-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]pyridine-2-carboxylicacid Example 23A Ethyl 4-iodo-5-methyl-1H-pyrrole-2-carboxylate

The title compound was prepared by following the procedure described forEXAMPLE 16E and replacing EXAMPLE 16D with ethyl5-methyl-1H-pyrrole-2-carboxylate.

Example 23B 4-iodo-5-methyl-1H-pyrrole-2-carboxylic acid

EXAMPLE 23A (1 g) in tetrahydrofuran (30 mL) and methanol (10 mL) wastreated with 2 N NaOH (20 mL) overnight. The reaction mixture was cooledto 0° C., acidified to pH 5, diluted with water (30 mL) and concentratedto remove the organic solvent. The precipitates were collected byfiltration, washed with water and dried over sodium sulfate to providethe title compound.

Example 23C 4-iodo-5-methyl-1H-pyrrole-2-carboxamide

To a solution of EXAMPLE 23B (7.7 g) in tetrahydrofuran (20 mL) at 0° C.was added carbonyldiimidazole (14.9 g). The resulting mixture wasstirred at room temperature for 2 hours. The reaction mixture was cooledto 0° C. and ammonium hydroxide (3 mL) was added. The mixture wasstirred at room temperature for 2 hours and concentrated. The residuewas dissolved in ethyl acetate, washed with brine and concentrated toprovide the title compound.

Example 23D 4-iodo-5-methyl-1H-pyrrole-2-carbonitrile

To a solution of EXAMPLE 23C (7.89 g) in DMF (80 mL) and pyridine (5 mL)at 0° C. was added dropwise oxalyl chloride (5.52 mL). The mixture wasstirred at 0° C. for 30 minutes and ice-water was added to quench thereaction. The resulting mixture was diluted with ethyl acetate andwashed with aqueous NaHCO₃ and water extensively. The organic layer wasdried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby flash column, eluting with dichloromethane to provide the titlecompound.

Example 23E5-cyano-2-methyl-3-iodo-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrole

EXAMPLE 23D (170 mg), 1-bromomethyladamantane (840 mg) andtetrabutylammonium bromide (171 mg) in N,N-dimethylformamide (20 mL) wastreated with sodium hydride (147 mg) at 80° C. overnight. The reactionmixture was cooled, diluted with ethyl acetate and washed with brine.The organic layer was concentrated. The residue was purified by flashchromatography (40% dichloromethane in hexanes) to provide the titlecompound.

Example 23F3-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]-6-[8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 23E for EXAMPLE20A in EXAMPLE 20B.

Example 23G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 23F for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42-7.53 (m, 3H),7.33-7.39 (m, 2H), 6.95 (d, 1H), 6.82 (s, 1H), 4.96 (s, 2H), 3.89 (t,2H), 3.74 (s, 2H), 3.01 (t, 2H), 2.09 (s, 3H), 1.96 (s, 3H), 1.62-1.69(m, 3H), 1.53-1.60 (m, 9H).

Example 243-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid Example 24A3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substitutingthiazolo[5,4-b]pyridin-2-amine for thiazolo[4,5-b]pyridine-2-amine inEXAMPLE 30D.

Example 24B3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 24A for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.98 (s,2H), 8.57-8.47 (m, 1H), 8.16 (d, 1H), 7.63 (d, 1H), 7.56-7.47 (m, 2H),7.45 (d, 1H), 7.38 (t, 1H), 7.27 (s, 1H), 6.96 (d, 1H), 4.96 (s, 2H),3.88 (t, 2H), 3.70 (s, 2H), 3.02 (t, 2H), 2.10 (s, 3H), 1.92 (s, 3H),1.71-142 (m, 12H).

Example 256-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-3,4′-bipyridine-2-carboxylicacid Example 25A2-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-4-iodo-pyridine

1-Adamantanemethanol (0.820 g) and 2-fluoro-4-iodopyridine (0.22 g) intetrahydrofuran (5 mL) was treated with sodium hydride (60% in mineraloil) (0.057) at room temperature for 6 hours. The reaction was quenchedwith ice-water and extracted with ethyl acetate (3×10 mL). The organiclayer was dried over MgSO₄, filtered, and concentrated. The residue waspurified by preparative TLC, eluting with petroleum ether/ethyl acetate(20/1) to provide the title compound.

Example 25B2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-6-[8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-[3,4′]bipyridinyl-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 25A for EXAMPLE20A in EXAMPLE 20B.

Example 25C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-3,4′-bipyridine-2-carboxylicacid

The title compound was synthesized by substituting EXAMPLE 25B forEXAMPLE 2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm12.89 (s, 1H), 8.09 (d, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.73 (d, 1H),7.63 (d, 1H), 7.44-7.49 (m, 2H), 7.34-7.39 (m, 2H), 7.00 (d, 1H), 6.90(dd, 1H), 6.72 (s, 1H), 5.01 (s, 2H), 3.92 (t, 2H), 3.86 (s, 2H), 3.02(t, 2H), 1.97 (s, 3H), 1.61-1.72 (m, 12H).

Example 266-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3-[2-(morpholin-4-yl)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 26A3-bromotricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl-1H-pyrazole

The title compound was prepared by substituting pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand 3-bromo-1-adamantanemethanol for 1-adamantanemethanol in EXAMPLE 2A.

Example 26B3-[2-(morpholin-4-yl)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 26A for EXAMPLE7A and 2-morpholinoethanol for methanol in EXAMPLE 7B.

Example 26C4-iodo-3-{[2-(morpholin-4-yl)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl}-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 26B for EXAMPLE3B and N-iodosuccinimide for N-bromosuccinimide in EXAMPLE 3C.

Example 26D tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((3-[2-(morpholin-4-yl)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 26C for EXAMPLE4A in EXAMPLE 4C.

Example 26E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3-[2-(morpholin-4-yl)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 26D for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(br. s, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.71 (m, 2H), 7.61 (d, 1H),7.55 (s, 1H), 7.41 (m, 4H), 6.95 (d, 1H), 4.95 (s, 2H), 3.90 (m, 6H),3.66 (m, 4H), 3.09 (m, 8H), 2.17 (m, 2H), 1.69 (m, 2H), 1.47 (m, 10H).

Example 276-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-3,4′-bipyridine-2-carboxylicacid Example 27A2-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-4-iodo-3-methyl-pyridine

1-Hydroxylmethyladamantane (249 mg) was dissolved in tetrahydrofuran(3.5 mL) and NaH (24 mg) was added. After the gas evolution ceased,2-fluoro-4-iodo-3-methylpyridine (237 mg) in tetrahydrofuran (1.5 mL)was added. The reaction mixture was stirred at room temperature for 0.5hours, quenched with H₂O and extracted with ethyl acetate. The combinedorganic layers were washed with brine and concentrated. The residue waspurified by preparative TLC, eluting with petroleum ether to provide thetitle compound.

Example 27B2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-6-[8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3′-methyl-[3,4′]bipyridinyl-2-carboxylicacid tert-butyl ester

The title compound was synthesized by substituting EXAMPLE 27A forEXAMPLE 20A in EXAMPLE 20B.

Example 27C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-3,4′-bipyridine-2-carboxylicacid

The title compound was synthesized by substituting EXAMPLE 27B forEXAMPLE 2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm7.88 (d, 1H), 7.71-7.73 (m, 1H), 7.44-7.47 (m, 1H), 7.28-7.35 (m, 3H),7.17-7.25 (m, 3H), 6.95 (d, 1H), 6.52 (d, 1H), 5.07-5.16 (m, 2H),3.81-3.84 (m, 4H), 3.04-3.05 (m, 2H), 1.89-1.93 (m, 6H), 1.61-1.69 (m,12H).

Example 286-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-yloxy]phenyl}pyridine-2-carboxylicacid Example 28A1-(3-bromo-2-methylphenoxy)tricyclo[3.3.1.1^(3,7)]decane

3-Bromo-2-methylphenol (1000 mg) and 1-bromoadamantane (2013 mg) wereadded to hexamethylphosphoramide (8 mL) and the mixture was heated in amicrowave reactor (Biotage) at 250° C. for 35 minutes. The solution wastaken up in diethyl ether, washed with water two times, washed withbrine, dried on anhydrous sodium sulfate, filtered, and concentrated.The crude material was purified by flash column chromatography on silicagel using 2% ethyl acetate (hexanes) increasing to 5% ethyl acetate(hexanes) to yield the title compound.

Example 28B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-yloxy]phenyl}pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 28A for EXAMPLE20A in EXAMPLE 20B.

Example 28C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-yloxy]phenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 28B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 12.55 (bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (m, 2H),7.50-7.32 (m, 4H), 7.08-6.95 (m, 3H), 6.73 (d, 1H), 4.98 (bs, 2H), 3.91(m, 2H), 3.03 (t, 2H), 2.13 (bs, 3H), 1.93 (s, 3H), 1.86 (m, 6H), 1.59(m, 6H).

Example 296-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 29A4-bromo-5-cyano-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazole

The title compound was prepared by substituting4-bromo-3-cyano-1H-pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 29B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 29A for EXAMPLE20A in EXAMPLE 20B.

Example 29C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 29B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(bs, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.68 (t, 2H), 7.63 (d, 1H),7.50-7.38 (m, 4H), 7.06 (d, 1H), 5.01 (bs, 2H), 3.97 (s, 2H), 3.93 (t,2H), 3.02 (t, 2H), 1.95 (bs, 3H), 1.68-1.50 (m, 12H).

Example 303-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[4,5-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid Example 30A methyl2-(5-bromo-6-(tert-butoxycarbonyl)pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylate

The title compound was prepared by substituting methyl1,2,3,4-tetrahydroisoquinoline-8-carboxylate for EXAMPLE 1C in EXAMPLE1E.

Example 30B2-[6-tert-butoxycarbonyl-5-(1-tricyclo[3.3.1.1^(3,7)]decan-1-ylmethyl-1pyrazol-4-yl)-pyridin-2-yl]-1,2,3,4-tetrahydro-isoquinoline-8-carboxylicacid methyl ester

The title compound was prepared by substituting EXAMPLE 30A for EXAMPLE14C in EXAMPLE 14D.

Example 30C 2-[6-carboxy-5-(1-tricyclo[3.3.1.1^(3,7)]decan-1-ylmethyl-1pyrazol-4-yl)-pyridin-2-yl]-1,2,3,4-tetrahydro-isoquinoline-8-carboxylicacid methyl ester

EXAMPLE 30B (2.3 g) was dissolved in tetrahydrofuran (4.0 mL) andmethanol (8.0 mL), and 1N LiOH (5.3 mL) was added. The mixture wasstirred at room temperature for six days. The reaction mixture wasdiluted with water (50 mL), 2N aqueous HCl (2.65 mL) was added, and themixture was stirred for a few minutes. The mixture was filtered, and thesolid was washed with water, and dried under high vacuum in the presenceof P₂O₅ overnight to provide the title compound.

Example 30D3-(5-methyl-1-tricyclo[3.3.1.1^(3,7)]decan-1-ylmethyl-1H-pyrazol-4-yl)-6-[8-(thiazolo[4,5-b]pyridin-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-pyridine-2-carboxylicacid tert-butyl ester

To a solution of EXAMPLE 30C (80 mg) and thiazolo[4,5-b]pyridine-2-amine(21 mg) in dichloromethane (1.5 mL) was added1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (40 mg)and 4-(dimethylamino)pyridine (26 mg). The mixture was stirred at roomtemperature overnight. The reaction mixture was then concentrated andpurified by chromatography on silica gel using 1/4 hexanes/ethyl acetateto provide the title compound.

Example 30E3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]decan-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-(thiazolo[4,5-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid

EXAMPLE 30D (37 mg) was dissolved in dichloromethane (1.5 mL) andtrifluoroacetic acid (1.5 mL). After stirring at room temperatureovernight, the reaction mixture was concentrated and triturated withdiethyl ether (5 mL) to provide the title compound. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ ppm 13.20 (br s, 1H), 8.61 (dd, 1H), 8.56 (dd,1H), 7.65 (d, 1H), 7.51 (d, 1H), 7.45 (d, 1H), 7.39 (m, 2H), 7.27 (s,1H), 6.96 (d, 1H), 4.97 (s, 2H), 3.89 (t, 2H), 3.70 (s, 2H), 3.02 (t,2H), 2.10 (s, 3H), 1.92 (br s, 3H), 1.64 (br d, 3H), 1.54 (br m, 9H).

Example 313-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[4,5-c]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid Example 31A3-(5-methyl-1-tricyclo[3.3.1.1^(3,7)]decan-1-ylmethyl-1H-pyrazol-4-yl)-6-[8-(thiazolo[4,5-c]pyridin-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substitutingthiazolo[4,5-c]pyridine-2-amine for thiazolo[4,5-b]pyridine-2-amine inEXAMPLE 30D.

Example 31B3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]decan-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-(thiazolo[4,5-c]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 31A for EXAMPLE30D in EXAMPLE 30E. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 13.34(br s, 1H), 9.30 (s, 1H), 8.59 (d, 1H), 8.45 (d, 1H), 7.65 (d, 1H), 7.50(d, 1H), 7.47 (d, 1H), 7.40 (t, 1H), 7.27 (s, 1H), 6.96 (d, 1H), 4.97(s, 2H), 3.89 (t, 2H), 3.70 (s, 2H), 3.02 (t, 2H), 2.10 (s, 3H), 1.92(br s, 3H), 1.64 (br d, 3H), 1.54 (br m, 9H).

Example 326-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 32A1-((3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl)-1H-pyrazole

The title compound was prepared by substituting(3,5-dimethyladamantan-1-yl)methanol for 1-adamantanemethanol andpyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 32B1-((3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl)-5-methyl-1H-pyrazole

To a solution of EXAMPLE 32A (2.44 g) in tetrahydrofuran (25 mL)/toluene(25 mL) was added n-butyllithium (7.49 mL) at −40° C. The reactionmixture was stirred for 60 minutes when CH₃I (1.873 mL) was added andthe stirring was continued for 2 hours at −40° C. The reaction mixturewas quenched with saturated ammonium chloride solution, extracted withethyl acetate, dried over magnesium sulfate, filtered, concentrated andpurified by flash chromotography (silica gel, 0%-15% ethylacetate/hexanes).

Example 32C3-bromo-1-((3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 32B for EXAMPLE3B in EXAMPLE 3C.

Example 32D tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 32C for EXAMPLE4A in EXAMPLE 4C.

Example 32E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 32D for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.48 (m, 3H), 7.40-7.31(m, 2H), 7.27 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.88 (d, 2H), 3.74(s, 2H), 3.01 (t, 2H), 2.09 (s, 3H), 2.04-1.97 (m, 1H), 1.33 (s, 2H),1.24 (s, 4H), 1.21-0.98 (m, 6H), 0.78 (s, 7H).

Example 336-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(1,1-dioxidothiomorpholin-4-yl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl})-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 33A4-(3-((4-iodo-1H-pyrazol-1-yl)methyl)tricyclo[3.3.1.1^(3,7)]dec-1-yl)-1,1-dioxidothiomorpholine

The title compound was prepared by substitutingthiomorpholine-1,1-dioxide for methanol in EXAMPLE 7B.

Example 33B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(1,1-dioxidothiomorpholin-4-yl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 33A for EXAMPLE4A in EXAMPLE 4C.

Example 33C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{3-(1,1-dioxidothiomorpholin-4-yl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl})-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 33B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(br. s, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.71 (m, 2H), 7.59 (m, 2H),7.41 (m, 4H), 6.95 (d, 1H), 4.95 (s, 2H), 3.88 (m, 4H), 3.01 (m, 2H),2.72 (m, 2H), 2.43 (m, 2H), 2.21 (m, 4H), 1.61 (m, 12H)

Example 346-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-2-methyl-1-[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)ethyl]-1H-pyrrol-3-yl}pyridine-2-carboxylicacid Example 34A5-cyano-2-methyl-1-[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)ethyl]-1H-pyrrole

The title compound was synthesized by substituting EXAMPLE 23D for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand adamantane-1-ethanol for 1-adamantanemethanol in EXAMPLE 2A.

Example 34B3-[5-cyano-2-methyl-1-[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)ethyl]-1H-pyrrol-3-yl]-6-[8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 34A for EXAMPLE20A in EXAMPLE 20B.

Example 34C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-2-methyl-1-[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)ethyl]-1H-pyrrol-3-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 34B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.41-7.51 (m, 3H),7.33-7.39 (m, 2H), 6.95 (d, 1H), 6.78 (s, 1H), 4.96 (s, 2H), 3.96-4.04(m, 2H), 3.89 (t, 2H), 3.01 (t, 2H), 2.10 (s, 3H), 1.95 (s, 3H),1.53-1.73 (m, 12H), 1.33-1.44 (m, 2H).

Example 35N-(1,3-benzothiazol-2-yl)-2-{5-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

The title compound was prepared by substituting EXAMPLE 23G for EXAMPLE3F in EXAMPLE 17. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 11.82 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.54 (d,1H), 7.42-7.50 (m, 2H), 7.32-7.40 (m, 2H), 7.00 (d, 1H), 6.82 (s, 1H),4.96 (s, 2H), 3.94 (t, 2H), 3.73 (s, 2H), 3.13 (s, 3H), 3.03 (t, 2H),2.10 (s, 3H), 1.95 (s, 3H), 1.50-1.70 (m, 12H).

Example 36N-(1,3-benzothiazol-2-yl)-2-{5-[5-cyano-2-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]-6-[(cyclopropylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

The title compound was prepared by substituting EXAMPLE 23G for EXAMPLE3F and cyclopropanesulfonamide for methanesulfonamide in EXAMPLE 17. ¹HNMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s, 1H), 11.74 (s, 1H),8.02 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.54 (d, 1H), 7.42-7.50 (m,2H), 7.32-7.40 (m, 2H), 7.01 (d, 1H), 6.82 (s, 1H), 4.99 (s, 2H), 3.93(t, 2H), 3.73 (s, 2H), 3.03 (t, 2H), 2.74-2.84 (m, 1H), 2.11 (s, 3H),1.94 (s, 3H), 1.52-1.68 (m, 12H), 0.99-1.05 (m, 2H), 0.87-0.95 (m, 2H).

Example 37N-(1,3-benzothiazol-2-yl)-2-{5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

The title compound was prepared by substituting EXAMPLE 16G for EXAMPLE3F in EXAMPLE 17. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(br. s, 1H), 11.81 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H),7.54 (d, 1H), 7.46 (m, 2H), 7.36 (m, 2H), 7.28 (s, 1H), 7.00 (d, 1H),4.96 (s, 2H), 3.93 (m, 2H), 3.80 (s, 3H), 3.12 (s, 3H), 3.08 (s, 3H),3.02 (m, 2H), 2.13 (m, 4H), 1.49 (m, 12H).

Example 386-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-methoxy-5,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 38A5-bromo-3,7-dimethyltricyclo[3.3.1.1^(3,7)]decane-1-carboxylic acid

In a 50 mL round-bottomed flask, bromine (3 mL) was cooled to 0° C. andiron (0.56 g) was added. The mixture was stirred at 0° C. for 30minutes. 3,5-dimethyladamantane-1-carboxylic acid (0.5 g) was added. Themixture was stirred at room temperature overnight. After adding ice and6N aqueous HCl (10 mL), ethyl acetate (20 mL), and saturated aqueousNa₂SO₃ were added. The aqueous layer was extracted twice with ethylacetate. The combined organic layers were washed with saturated Na₂SO₃(50 mL, 3×) and dried over Na₂SO₄. After filtration and removal of thesolvent, the product was used directly in the next step.

Example 38B 5-bromo-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-ylmethanol

The title compound was prepared by substituting EXAMPLE 38A for3,5,8-trimethyl-1-adamantane carboxylic acid in EXAMPLE 9A.

Example 38C1-(5-bromo-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-1H-pyrazole

The title compound was prepared by substituting pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand EXAMPLE 38B for 1-adamantanemethanol in EXAMPLE 2A.

Example 38D1-(5-methoxy-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 38C for EXAMPLE7A in EXAMPLE 7B.

Example 38E1-(5-methoxy-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 38C for EXAMPLE3A in EXAMPLE 3B.

Example 38F4-bromo-1-(5-methoxy-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 38E for EXAMPLE3B in EXAMPLE 3C.

Example 38G tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-(5-methoxy-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 38F for EXAMPLE4A in EXAMPLE 4C.

Example 38H6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-(5-methoxy-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 38G for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84(br. s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.42 (m, 5H),7.28 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.82 (s, 2H),3.08 (s, 3H), 3.01 (t, 2H), 2.09 (s, 3H), 1.34 (s, 2H), 1.12 (m, 10H),0.85 (s, 6H).

Example 39N-(1,3-benzothiazol-2-yl)-2-{5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[(morpholin-4-ylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

The title compound was prepared by substituting EXAMPLE 16G for EXAMPLE3F and morpholine-4-sulfonamide for methanesulfonamide in EXAMPLE 17. ¹HNMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (br. s, 1H), 11.64 (s,1H), 8.02 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.44 (m, 5H), 7.27 (s,1H), 7.01 (d, 1H), 4.99 (s, 2H), 3.91 (t, 2H), 3.79 (s, 2H), 3.12 (m,4H), 3.08 (s, 3H), 3.02 (t, 2H), 2.12 (m, 5H), 1.48 (m, 12H).

Example 40N-(1,3-benzothiazol-2-yl)-2-[5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-{[(trifluoromethyl)sulfonyl]carbamoyl}pyridin-2-yl]-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

The title compound was prepared by substituting EXAMPLE 16G for EXAMPLE3F and trifluoromethanesulfonamide for methanesulfonamide in EXAMPLE 17.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (br. s, 1H), 8.03 (d,1H), 7.79 (d, 1H), 7.64 (d, 1H), 7.57 (d, 1H), 7.47 (m, 2H), 7.35 (m,3H), 6.98 (d, 1H), 4.95 (s, 2H), 3.92 (t, 2H), 3.05 (m, 5H), 2.13 (m,5H), 1.48 (m, 12H).

Example 41N-(1,3-benzothiazol-2-yl)-2-{6-[(cyclopropylsulfonyl)carbamoyl]-5-(1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

The title compound was prepared by substituting EXAMPLE 16G for EXAMPLE3F and cyclopropanesulfonamide for methanesulfonamide in EXAMPLE 17. ¹HNMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (br. s, 1H), 11.74 (s,1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.53 (d, 1H), 7.46 (m,2H), 7.36 (m, 2H), 7.29 (s, 1H), 7.01 (d, 1H), 4.98 (s, 2H), 3.93 (t,2H), 3.79 (s, 3H), 3.08 (s, 3H), 3.03 (t, 2H), 2.11 (m, 5H), 1.50 (m,12H), 0.96 (m, 4H).

Example 426-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-chloro-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 42A5-chloro-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazole

The title compound was prepared by substituting hexachloroethane foriodomethane in EXAMPLE 3B.

Example 42B4-bromo-5-chloro-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 42A for EXAMPLE3B in EXAMPLE 3C.

Example 42C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-chloro-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 42B for EXAMPLE20A in EXAMPLE 20B.

Example 42D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-chloro-1-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 42C for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.59 (d, 1H),7.51-7.43 (m, 3H), 7.37 (m, 2H), 7.00 (d, 1H), 4.98 (bs, 2H), 3.93 (t,2H), 3.81 (s, 2H), 3.02 (t, 2H), 1.93 (bs, 3H), 1.68-1.50 (m, 12H).

Example 436-[8-(1,3-benzothiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 43A2-(tert-butoxycarbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline-8-carboxylicacid

To a solution of2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid(2.25 g) and tetramethylethylenediamine (1.347 mL) in tetrahydrofuran(40 mL) was added dropwise t-butyllithium (1.6M, 15.21 mL) at −78° C.The mixture was stirred at −78° C. for 40 minutes. To the resultingmixture was added iodomethane (5.07 mL) dropwise and the mixture wasstirred at −78° C. for 3 hours, followed by stirring at room temperatureovernight. The reaction mixture was quenched with saturated ammoniumchloride. The reaction mixture was extracted with ethyl acetate (150mL), washed with brine (40 mL×3), dried over Na₂SO₄, filtered, andconcentrated. The crude product was purified by flash chromatography(silica gel, 10% methanol/dichloromethane).

Example 43B tert-butyl8-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of EXAMPLE 43A (400 mg), PyBOP(benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, 714mg), triethylamine (0.383 mL) and benzo[d]thiazol-2-amine (247 mg) indichloromethane (10 mL) was stirred overnight at room temperature. Themixture was diluted with ethyl acetate (100 mL), washed with brine (30mL×3), dried over Na₂SO₄, filtered, concentrated and purified by flashchromatography (silica gel, petroleum ether/ethyl acetate=1/1).

Example 43CN-(benzo[d]thiazol-2-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

A solution of EXAMPLE 43B (150 mg) in dichloromethane (10 mL) wastreated with TFA (1 mL). The reaction mixture was stirred for 2 hours at30° C. The reaction mixture was diluted with ethyl acetate (100 mL),washed with saturated NaHCO₃, brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by flash chromotography(silica gel, dichloromethane/methanol=10/1).

Example 43D methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2(1H)-yl)-3-bromopicolinate

A solution of EXAMPLE 43C (1 g), methyl 3-bromo-6-fluoropicolinate(0.715 g) and triethylamine (0.775 mL) in 12 mL DMSO was heated at 70°C. overnight followed by heating at 105° C. for 4 hours. The reactionmixture was diluted with ethyl acetate, washed 3 times with water,washed with brine, dried over Na₂SO₄, filtered, and concentrated. Thecrude material was purified by flash chromotography (silica gel, 5-25%ethyl acetate/hexanes).

Example 43E methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 43D for EXAMPLE4A and EXAMPLE 3D for EXAMPLE 4B in EXAMPLE 4C.

Example 43F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 43E for EXAMPLE14A in EXAMPLE 14B. ¹H NMR (dimethylsulfoxide-d₆) δ ppm 12.67 (s, 1H),8.01 (d, 1H), 7.78 (d, 1H), 7.55 (d, 1H), 7.51-7.39 (m, 3H), 7.34 (dt,3H), 6.77 (d, 1H), 6.13 (d, 1H), 4.11-3.96 (m, 1H), 3.70 (s, 2H),3.66-3.54 (m, 2H), 3.06 (t, 2H), 2.13 (s, 3H), 1.93 (s, 3H), 1.67 (s,1H), 1.63 (s, 2H), 1.58 (s, 2H), 1.53 (s, 6H), 1.41 (d, 3H).

Example 446-[8-(1,3-benzothiazol-2-ylcarbamoyl)-1,1-dideutero-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 44A2-(tert-butoxycarbonyl)-1,1-dideutero-1,2,3,4-tetrahydroisoquinoline-8-carboxylicacid

To a tetrahydrofuran (40 mL) solution of2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid(5 g) and tetramethylethylenediamine (2.99 mL) was added dropwiset-butyllithium (1.7 M, 39.4 mL) at −78° C. The mixture was stirred at−78° C. for 3 hours. To the resulting mixture, D₂O (0.979 mL) was addeddropwise and the reaction mixture was stirred at −78° C. for 2 hours.The mixture was diluted with ethyl acetate (150 mL), washed with brine,dried over Na₂SO₄, filtered, and concentrated. The crude product wasused in next step without further purification. This procedure wasrepeated on the same material 5 times.

Example 44B tert-butyl8-(benzo[d]thiazol-2-ylcarbamoyl)-1,1-dideutero-1,2,3,4-tetrahydroisoquinoline-carboxylate

A mixture of triethylamine (1.753 g),(1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphoniumhexafluorophosphate(V) (4.51 g), EXAMPLE 44A (2.42 g) andbenzo[d]thiazol-2-amine (1.952 g) in dichloromethane (50 mL) was stirredovernight at 30° C. The reaction mixture was diluted withdichloromethane (200 mL), washed with brine, dried over Na₂SO₄,filtered, and concentrated. The crude product was purified by flashchromotography (silica gel, 30%—50% ethyl acetate/petroleum ether).

Example 44CN-(benzo[d]thiazol-2-yl)-1,1-dideutero-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

The title compound was prepared by substituting EXAMPLE 44B for EXAMPLE43B in EXAMPLE 43C.

Example 44D methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-1,1-dideutero-1,2,3,4-tetrahydroisoquinolin-yl)-3-bromopicolinate

The title compound was prepared by substituting EXAMPLE 44C for EXAMPLE43C in EXAMPLE 43D.

Example 44E methyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)(1,1-diduetero-1,2,3,4-tetrahydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 44D for EXAMPLE4A and EXAMPLE 3D for EXAMPLE 4B in EXAMPLE 4C.

Example 44F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)(1,1-²H₂)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 44E for EXAMPLE14A in EXAMPLE 14B. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.79(s, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.52-7.40 (m, 3H),7.36 (m, 2H), 7.26 (s, 1H), 6.94 (d, 1H), 4.02 (s, 1H), 3.89 (dd, 2H),3.70 (s, 2H), 3.01 (t, 2H), 2.10 (s, 3H), 1.92 (s, 3H), 1.67 (s, 1H),1.63 (s, 2H), 1.57 (s, 2H), 1.52 (s, 6H).

Example 456-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-(2-methoxyethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 45A1-(5-(2-methoxyethoxy)-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 26A for EXAMPLE7A and 2-methoxyethanol for methanol in EXAMPLE 7B.

Example 45B1-((5-2-methoxyethoxy)-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 45A for EXAMPLE3A in EXAMPLE 3B.

Example 45C4-bromo-1-((5-2-methoxyethoxy)-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 45B for EXAMPLE3B in EXAMPLE 3C.

Example 45D tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-(5-(2-methoxyethoxy)-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 45C for EXAMPLE4A in EXAMPLE 4C.

Example 45E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-(5-(2-methoxyethoxy)-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 45D for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(br. s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42 (m, 5H),7.28 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.78 (s, 2H),3.21 (s, 3H), 3.01 (t, 2H), 2.11 (m, 5H), 1.50 (m, 12H).

Example 466-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclooctyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 46A methyl cyclooctanecarboxylate

To a solution of cyclooctanecarbaldehyde (5.0 g) in methanol (300 mL)was added Oxone (22 g). The mixture was stirred at room temperature for18 hours. The reaction mixture was concentrated under vacuum and theresidue was diluted with ethyl acetate (300 mL) and washed with 1Naqueous HCl, water, and brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give the crude product.

Example 46B methyl 1-(2-methoxyethyl)cyclooctanecarboxylate

To a cooled (−78° C.) solution of lithium diisopropylamide (2.0M, 20 mL)in tetrahydrofuran (20 mL) was added EXAMPLE 46A (5.27 g) intetrahydrofuran (20 mL). The mixture was stirred at −78° C. for 30minutes and a solution of 1-bromo-3-methoxypropane (4.3 g) intetrahydrofuran (10 mL) was added to the mixture. The mixture wasstirred overnight and the temperature was allowed to warm up to roomtemperature. The mixture was quenched with aqueous NH₄Cl and extractedwith ethyl acetate (300 mL) and washed with water (3×) and brine anddried over Na₂SO₄. Filtration and concentration of the solvent gave thecrude product which was used in the next reaction without furtherpurification.

Example 46C (1-(2-methoxyethyl)cyclooctyl)methanol

A solution of EXAMPLE 46B (6.5 g) in ether (50 mL) was added dropwise toa suspension of LiAlH₄ (1.2 g) in ether (60 mL). Once the addition wasfinished, the mixture was refluxed for 90 minutes, cooled to 0° C. and2N aqueous NaOH (50 mL) was added slowly. The mixture was then extractedwith ethyl acetate (300 mL) and the organic layer was washed with brineand dried over Na₂SO₄. Filtration and evaporation of the solventprovided the title compound.

Example 46D 1-((1-(2-methoxyethyl)cyclooctyl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 46C for1-adamantanemethanol and 1H-pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 46E1-((1-(2-methoxyethyl)cyclooctyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 46D for EXAMPLE3A in EXAMPLE 3B.

Example 46F4-iodo-1-((1-(2-methoxyethyl)cyclooctyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 46E for EXAMPLE16D in EXAMPLE 16E.

Example 46G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclooctyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 46F for EXAMPLE4A in EXAMPLE 4B, then substituting that product for EXAMPLE 2B inEXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ: ppm 12.85 (s, 1H),8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.40 (m, 6H), 7.29 (s, 1H),6.95 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.80 (s, 3H), 3.44 (t, 2H),3.21 (s, 3H), 3.00 (t, 2H), 2.10 (s, 3H), 1.34 (m, 16H).

Example 476-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylamino]phenyl}pyridine-2-carboxylicacid Example 47A2-(tricyclo[3.3.1.1^(3,7)]dec-1-ylamino)-6-bromo-benzonitrile

2-Bromo-6-fluorobenzonitrile (300 mg) and 1-adamantane (295 mg) wereadded to dimethyl sulfoxide (5 mL). The solution was stirred untilreactants had dissolved. The solution was then heated in a microwavereactor (Biotage) at 180° C. for 20 minutes. The solution was added toethyl ether, and washed with 1 M aqueous HCl three times, and washedwith brine. The combined organic layers were dried on anhydrous sodiumsulfate, filtered, and concentrated. The crude material was purified byflash column chromatography on silica gel using 5% ethyl acetate(hexanes) to yield the product.

Example 47B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylamino]phenyl}pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 47A for EXAMPLE20A in EXAMPLE 20B.

Example 47C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylamino]phenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 47B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 8.03 (d,1H), 7.79 (d, 1H), 7.64-7.58 (m, 2H), 7.49-7.29 (m, 6H), 7.06 (dd, 1H),7.02 (d, 1H), 6.52 (d, 1H), 5.01 (bs, 2H), 3.91 (m, 2H), 3.03 (m, 2H),2.10 (bs, 3H), 1.98 (bs, 6H), 1.68 (m, 6H).

Example 486-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl]phenyl}pyridine-2-carboxylicacid Example 48A2-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl)-6-bromo-benzonitrile

1-Adamantanethiol (278 mg) was dissolved in dimethyl sulfoxide (10 mL).Sodium hydride (60% in mineral oil, 42 mg) was added, and the solutionwas stirred at room temperature for 20 minutes.2-Bromo-6-fluorobenzonitrile (300 mg) was added and the solution washeated to 130° C. for 1 hour. The solution was cooled, added to diethylether, washed with 1 M aqueous HCl three times, washed with brine, anddried over anhydrous sodium sulfate. After filtration, the solvent wasremoved under vacuum to yield the title compound.

Example 48B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl]phenyl}pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 48A for EXAMPLE20A in EXAMPLE 20B.

Example 48C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl]phenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 48B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.68-7.60 (m, 3H), 7.49-7.32 (m,6H), 7.08 (d, 1H), 5.04 (bs, 2H), 3.98 (t, 2H), 3.05 (t, 2H), 2.00 (bs,3H), 1.83 (bs, 4H), 1.79-1.72 (m, 2H), 1.60 (m, 6H).

Example 496-[8-(imidazo[1,2-a]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 49A6-[8-(imidazo[1,2-a]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substitutingimidazo[1,2-a]pyridine-2-amine for thiazolo[4,5-b]pyridine-2-amine inEXAMPLE 30D.

Example 49B6-[8-(imidazo[1,2-a]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 49A for EXAMPLE1F in EXAMPLE 1G. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 11.66 (brs, 1H), 8.76 (d, 1H), 8.36 (s, 1H), 7.72 (d, 1H), 7.60 (dd, 1H), 7.55(dd, 1H), 7.51 (d, 1H), 7.42 (d, 1H), 7.37 (t, 1H), 7.27 (s, 1H), 7.24(t, 1H), 6.93 (d, 1H), 4.96 (s, 2H), 3.88 (t, 2H), 3.71 (s, 2H), 3.01(t, 2H), 2.10 (s, 3H), 1.93 (br s, 3H), 1.65 (br d, 3H), 1.54 (br m,9H).

Example 506-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylicacid Example 50AN-(3-bromo-2-methylphenyl)tricyclo[3.3.1.1^(3,7)]decane-1-carboxamide

3-Bromo-2-methylaniline (800 mg) and diisopropylethylamine (1667 mg)were added to dichloromethane (12 mL). 1-Adamantanecarbonyl chloride(940 mg) was added and the solution was stirred at room temperature for16 hours. The solution was diluted with 50% ethyl acetate (hexanes),washed three times with 1 M aqueous HCl, washed with brine, dried overanhydrous sodium sulfate, and filtered. The solvent volume was partiallyreduced under vacuum, and the solid material precipitated out ofsolution, which was isolated by filtration to provide the titlecompound.

Example 50B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 50A for EXAMPLE20A in EXAMPLE 20B.

Example 50C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 50B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(bs, 1H), 8.82 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H),7.49-7.32 (m, 5H), 7.17-7.09 (m, 2H), 7.00 (d, 1H), 6.90 (dd, 1H), 4.99(bs, 2H), 3.96 (t, 2H), 3.03 (t, 2H), 2.00 (bs, 3H), 1.90 (bs, 9H), 1.69(bs, 6H).

Example 516-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfamoyl]phenyl}pyridine-2-carboxylicacid Example 51A3-bromo-2-methyl-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)benzenesulfonamide

3-Bromo-2-methylbenzene-1-sulfonyl chloride (300 mg) and1-adamantanamine (185 mg) were dissolved in dichloromethane (4 mL).Diisopropylethylamine (432 mg) was added, and the solution was stirredat room temperature for 16 hours. The solution was diluted with 70%ethyl acetate (hexanes), washed three times with 1 M aqueous HCl, washedwith brine, and dried over anhydrous sodium sulfate. After filtration,the solvent was removed to yield the product.

Example 51B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 51A for EXAMPLE20A in EXAMPLE 20B.

Example 51C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfamoyl]phenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 51B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(bs, 1H), 12.58 (bs, 1H), 8.03 (d, 1H), 7.89 (dd, 1H), 7.79 (d, 1H),7.66-7.58 (m, 1H), 7.51-7.30 (m, 6H), 7.24 (dd, 1H), 7.03 (d, 1H), 5.01(bs, 2H), 3.95 (t, 2H), 3.04 (t, 2H), 2.32 (bs, 3H), 1.91 (m, 3H), 1.70(m, 6H), 1.58-1.44 (m, 6H).

Example 526-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylicacid Example 52AN-(3-bromo-2-methylphenyl)-N-methyltricyclo[3.3.1.1^(3,7)]decane-1-carboxamide

3-Bromo-N,2-dimethylaniline (300 mg) and diisopropylethylamine (581 mg)were added to 1,2-dichloroethane (5 mL). 1-Adamantanecarbonyl chloride(328 mg) was added and the solution was heated at 50° C. for three days.The solution was diluted with 70% ethyl acetate (hexanes), washed threetimes with 1M aqueous HCl, washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated. The crude material waspurified by flash column chromatography on silica gel using 10% ethylacetate (hexanes) to yield the title compound.

Example 52B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 52A for EXAMPLE20A in EXAMPLE 20B.

Example 52C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 52B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 8.03 (d,1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.50-7.32 (m, 5H), 7.24-7.14 (m, 2H),7.04 (dd, 1H), 7.01 (d, 1H), 5.00 (bs, 2H), 3.93 (t, 2H), 3.04 (t, 2H),2.98 (s, 3H), 1.91 (s, 3H), 1.82-1.71 (m, 6H), 1.61-1.41 (m, 9H).

Example 536-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 53A1-(5-(tetrahydropyran-4-ylmethoxy)-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 26A for EXAMPLE7A and (tetrahydro-2H-pyran-4-yl)methanol for methanol in EXAMPLE 7B.

Example 53B1-(5-(tetrahydropyran-4-ylmethoxy)-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 53A for EXAMPLE3A in EXAMPLE 3B.

Example 53C4-bromo-1-(5-(tetrahydropyran-4-ylmethoxy)-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 53B for EXAMPLE3B in EXAMPLE 3C.

Example 53D tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-(5-(tetrahydropyran-4-ylmethoxy)-3,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 53C for EXAMPLE4A in EXAMPLE 4C.

Example 53E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 53D for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84(br. s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.47 (m, 3H),7.35 (m, 2H), 7.27 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H),3.80 (m, 4H), 3.22 (m, 6H), 3.01 (t, 2H), 2.11 (m, 5H), 1.51 (m, J=4.00Hz, 15H).

Example 546-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbamoyl]phenyl}pyridine-2-carboxylicacid Example 54A 3-bromo-2-methyl-benzoyl chloride

3-Bromo-2-methylbenzoic acid (2000 mg) was added to dichloromethane (50mL) and N,N-dimethylformamide (1 mL). Oxalyl chloride (649 mg) was addedand the solution was stirred for three minutes. The mixture was washedwith 1 M aqueous HCl three times, washed with brine, and dried onanhydrous sodium sulfate. After filtration, the solvent was removedunder vacuum to yield the product.

Example 54B3-bromo-2-methyl-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)benzamide

The title compound was prepared by substituting 1-adamananamine for3-bromo-2-methylaniline and EXAMPLE 54A for 1-adamantanecarbonylchloride in EXAMPLE 50A.

Example 54C tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbamoyl]phenyl}pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 54B for EXAMPLE20A in EXAMPLE 20B.

Example 54D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbamoyl]phenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 54C for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 8.03 (d,1H), 7.79 (d, 1H), 7.69 (s, 1H), 7.63 (d, 1H), 7.50-7.32 (m, 5H),7.17-7.14 (m, 2H), 7.05 (t, 1H), 6.99 (d, 1H), 4.99 (bs, 2H), 3.93 (t,2H), 3.03 (t, 2H), 2.04 (bs, 12H), 1.64 (bs, 6H).

Example 556-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]amino}phenyl)pyridine-2-carboxylicacid Example 55A3-bromo-N,2-dimethyl-N-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)aniline

EXAMPLE 52A (232 mg) was dissolved in tetrahydrofuran (3 mL) and borane(1 M in tetrahydrofuran, 2.6 mL) was added. The solution was stirred atroom temperature for 16 hours and was quenched slowly with methanol.Aqueous HCl (4M, 6 mL) was added and the solution was stirred at roomtemperature for four hours. The pH was adjusted to 9 using sodiumcarbonate and the solution was extracted with diethyl ether. The extractwas washed with brine and dried on anhydrous sodium sulfate. Afterfiltration the solvent was removed under vacuum to yield the product.

Example 55B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]amino}phenyl)pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 55A for EXAMPLE20A in EXAMPLE 20B.

Example 55C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]amino}phenyl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 55B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.89(bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.50-7.32 (m, 5H),7.20-7.05 (m, 2H), 6.98 (d, 1H), 6.70 (d, 1H), 4.98 (bs, 2H), 3.92 (t,2H), 3.03 (t, 2H), 2.77 (bs, 2H), 2.61 (bs, 3H), 2.07 (bs, 3H), 1.87(bs, 3H), 1.66-1.50 (m, 6H), 1.43 (bs, 6H).

Example 566-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[2-(2-methoxyethyl)tricyclo[3.3.1.1^(3,7)]dec-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 56A methyl tricyclo[3.3.1.1^(3,7)]decane-2-carboxylate

To a solution of adamantane-2-carboxylic acid 1 (0.486 g, 2.70 mmol) inethyl acetate (10 mL)/methanol (5 mL) was dropwise added(trimethylsilyl)diazomethane (1.348 ml, 2.70 mmol) and the mixture wasstirred at room temperature for 14 hours. The reaction mixture wasconcentrated and purified by flash chromotography (silica 40 g, 0%-30%ethyl acetate/hexanes).

Example 56B methyl2-(2-methoxyethyl)tricyclo[3.3.1.1^(3,7)]decane-2-carboxylate

To a solution of EXAMPLE 56A (0.314 g) in tetrahydrofuran (5 mL) wasadded dropwise lithium diisopropylamide (1.401 mL) at −78° C. Thereaction mixture was stirred for 60 minutes and 2-bromoethyl methylether (0.562 g) was added. The reaction mixture was slowly warmed up toroom temperature, stirred at room temperature overnight, quenched withsaturated aqueous NH₄Cl solution (2 mL), and extracted with ether. Thecombined organic layer was dried over Na₂SO₄, filtered, concentrated andpurified by flash chromotography (silica 40 g, 0%-30% ethylacetate/hexanes).

Example 56C [2-(2-methoxyethyl)tricyclo[3.3.1.1^(3,7)]dec-2-yl]methanol

To a solution of EXAMPLE 56B (135 mg) in tetrahydrofuran (5 mL) wasadded dropwise lithium aluminum hydride (0.535 mL) at room temperature.The reaction mixture was stirred for 14 hours and sodium hydroxide(0.324 mL) was carefully added. The reaction mixture was stirred at roomtemperature for 60 minutes, filtered and concentrated.

Example 56D1-{[2-(2-methoxyethyl)tricyclo[3.3.1.1^(3,7)]dec-2-yl]methyl}-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 56C for1-adamantanemethanol and pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 56E4-bromo-1-{[2-(2-methoxyethyl)tricyclo[3.3.1.1^(3,7)]dec-2-yl]methyl}-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 56D for EXAMPLE3B in EXAMPLE 3C.

Example 56F tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-{[2-(2-methoxyethyl)tricyclo[3.3.1.1^(3,7)]dec-2-yl]methyl}-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 56E for EXAMPLE4A in EXAMPLE 4C.

Example 56G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[2-(2-methoxyethyl)tricyclo[3.3.1.1^(3,7)]dec-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 56F for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 8.04 (d,1H), 7.80 (d, 1H), 7.69 (d, 2H), 7.61 (d, 1H), 7.54 (s, 1H), 7.51-7.45(m, 1H), 7.43 (d, 1H), 7.35 (dd, 2H), 6.94 (d, 1H), 4.94 (s, 2H), 4.33(s, 2H), 3.86 (t, 2H), 3.47 (d, 2H), 3.29-3.22 (m, 2H), 3.19 (s, 3H),3.00 (t, 2H), 2.33-2.24 (m, 2H), 2.01 (d, 2H), 1.90 (s, 1H), 1.82 (s,1H), 1.67 (s, 2H), 1.56 (dd, 8H).

Example 576-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-1,2,3-triazol-4-yl]pyridine-2-carboxylicacid Example 57A 1-(azidomethyl)tricyclo[3.3.1.1^(3,7)]decane

1-Adamantanemethanol (500 mg) was dissolved in dichloromethane (15 mL).The solution was chilled in an ice bath and triethylamine (0.587 mL) wasadded, followed by methanesulfonyl chloride (0.258 mL). The reactionmixture was stirred for 4 hours at 0° C., then transferred to aseparatory funnel and rinsed with 1N aqueous HCl (15 mL), saturatedaqueous NaHCO₃ (15 mL) and brine (15 mL). The organic extracts weredried (Na₂SO₄), filtered, and concentrated. A portion of the resultingcrude mesylate (293 mg) and sodium azide (390 mg) were combined inN,N-dimethylformamide (1.2 mL) and the reaction mixture was heated to120° C. overnight, then cooled to room temperature and partitionedbetween ethyl acetate (3×15 mL) and water (20 mL). The organic extractswere dried (Na₂SO₄), filtered, and concentrated to provide the titlecompound, which was used in the next step without further purification.

Example 57B1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-5-methyl-4-(tributylstannyl)-1H-1,2,3-triazole

EXAMPLE 57A (224 mg), tributyl-n-propynyltin (390 mg) and toluene (2 mL)were combined in a sealed reaction vessel and heated to 130° C.overnight. The reaction mixture was placed atop a column and purified byflash chromatography on silica gel eluting with 0-15% ethyl acetate inhexanes to provide the title compound.

Example 57C methyl 6-amino-3-bromopicolinate

To a solution of 6-amino-3-bromopicolinic acid (30 g) in ethyl acetate(300 mL) and methanol (300 mL) was added TMS-diazomethane (70 mL, 2M inhexanes) and the reaction mixture was stirred for 3 days. The mixturewas concentrated, taken up in ether (500 mL) and washed with aqueousNa₂CO₃ solution (twice), then washed with brine, dried over sodiumsulfate, filtered and concentrated to provide the title compound.

Example 57D methyl 3-bromo-6-fluoropicolinate

To a solution of nitrosonium terafluoroborate (17.8 g) indichloromethane (100 mL) at 5° C. was added EXAMPLE 57C (26.1 g) indichloromethane (250 mL) over 1 hour. The reaction mixture was stirredan additional 30 minutes at 5° C., and allowed to warm to roomtemperature overnight. The reaction mixture was quenched with pH 7buffer (100 mL), and neutralized with solid potassium carbonate. Theresulting mixture was extracted with ether (twice), and the combinedorganic extracts were washed with brine, dried over sodium sulfate,filtered and concentrated. The residue was chromatographed on silica gelusing 1-10% ethyl acetate in hexanes to provide the title compound.

Example 57E methyl3-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-5-methyl-1H-1,2,3-triazol-4-yl)-6-fluoropicolinate

EXAMPLE 57B (333 mg), EXAMPLE 57D (178 mg) and PdCl₂(PPh₃)₂ (22 mg) werecombined in a sealed tube with N,N-dimethylformamide (1.3 mL) and themixture was sparged with nitrogen and then heated to 100° C. overnight.Saturated aqueous KF (2 mL) and ethyl acetate (2 mL) were added and themixture was stirred for 1 hour, and filtered through diatomaceous earth,rinsing the filter cake with ethyl acetate (20 mL). The filtrate wasplaced into a separatory funnel and the layers were separated. Theaqueous layer was extracted with ethyl acetate (2×25 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered, concentrated, andpurified by flash chromatography on silica gel using 0 to 50% ethylacetate in hexanes to provide the title compound.

Example 57F methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-5-methyl-1H-1,2,3-triazol-4-yl)picolinate

EXAMPLE 1C (110 mg), EXAMPLE 57E (93 mg) and cesium carbonate (394 mg)were combined in DMSO (1.2 mL) and the mixture was heated to 65° C.overnight. The reaction mixture was then partitioned between ethylacetate (3×10 mL) and water (10 mL). The organic extracts were dried(Na₂SO₄), filtered, and concentrated, then purified by flashchromatography using 0 to 70% ethyl acetate in hexanes to provide thetitle compound.

Example 57G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-1,2,3-triazol-4-yl]pyridine-2-carboxylicacid

Example 57F (83 mg) was dissolved in dioxane (1 mL) and LiOH (1M inwater, 0.616 mL) was added. The mixture was heated to 60° C. for 3hours, then cooled to room temperature and diluted with 1N NaH₂PO₄ (25mL) and extracted with ethyl acetate (three times). The organic extractswere dried (Na₂SO₄), filtered, and concentrated. The residue waspurified by flash chromatography on silica gel eluting with 0 to 10%methanol in dichloromethane to provide the title compound. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ ppm 12.68-12.90 (br m, 2H), 8.04 (d, 1H),7.79 (d, 1H), 7.67 (d, 1H), 7.62 (d, 1H), 7.42-7.51 (m, 2H), 7.31-7.41(m, 2H), 7.00 (d, 1H), 5.00 (s, 2H), 3.89-3.97 (m, 4H), 3.02 (t, 2H),2.16 (s, 3H), 1.94 (s, 3H), 1.53-1.69 (m, 6H), 1.52 (s, 6H).

Example 586-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid Example 58A3-iodo-5-cyano-1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-2-methyl-1H-pyrrole

The title compound was prepared by substituting3-methoxyadamantane-1-methanol for adamantane-1-ethanol and EXAMPLE 23Dfor3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 58B6-[8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[5-cyano-1-(3-methoxy-adamantan-1-ylmethyl)-2-methyl-1H-pyrrol-3-yl]-pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 58A for EXAMPLE20A in EXAMPLE 20B.

Example 58C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[3-methoxytricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 58B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51 (d, 1H), 7.42-7.50(m, 2H), 7.33-7.39 (m, 2H), 6.95 (d, 1H), 6.83 (s, 1H), 4.96 (s, 2H),3.89 (t, 2H), 3.82 (s, 2H), 3.10 (s, 3H), 3.01 (t, 2H), 2.18 (s, 2H),2.09 (s, 3H), 1.40-1.65 (m, 12H).

Example 596-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 59A1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-4-chloro-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 13A for1-adamantanemethanol and 4-chloro-1H-pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 59B1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-4-chloro-5-methyl-1H-pyrazole

A solution of EXAMPLE 59A (0.25 g) in tetrahydrofuran (3 mL) was cooledto −78° C. butyllithium was (0.48 mL) added dropwise. Additionaltetrahydrofuran (2 mL) was added and the reaction mixture was stirredfor 1 hour at −78° C. To the reaction mixture was added iodomethane(0.08 mL) in one portion and the reaction was allowed to warm to 0° C.After 30 minutes, the reaction was diluted with ether (50 mL), washedwith water (30 mL) and brine (30 mL), dried over magnesium sulfate,filtered, and concentrated. Silica gel chromatography eluting with agradient of 3% to 20% ethyl acetate/hexanes provided the title compound.

Example 59C1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-5-methyl-2-yl)-1H-pyrazole

A solution of EXAMPLE 59B (0.13 g),4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.13 mL), triethylamine (0.20mL), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.04 g) andbis(benzonitrile)palladium(II) chloride (6 mg) was heated in dioxane(2.5 mL) at 105° C. After 2 hours, the reaction mixture was diluted withethyl acetate and washed with water and dried over magnesium sulfate.After filtration and concentration, silica gel chromatography elutingwith a gradient of 1.5% to 15% ethyl acetate/hexanes provided the titlecompound.

Example 59D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

A solution of a 1:1 ratio of dioxane and water was degassed withnitrogen for 45 minutes. This solution (5 mL) was added to EXAMPLE 1E(0.31 g), EXAMPLE 59C (0.22 g), potassium phosphate (0.41 g),tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.014 g) and1,3,5,7-tetramethyl-6-tetradecane-2,4,8-trioxa-6-phosphaadamantane(0.023 g). The mixture was degassed and heated to 90° C. under nitrogenovernight. The reaction mixture was cooled, diluted with ethyl acetate(100 mL) and washed with water (three×50 mL) and brine (50 mL), driedover magnesium sulfate, filtered and concentrated. Silica gelchromatography eluting with a gradient of 5% to 100% ethylacetate/hexanes gave the desired ester. The ester was dissolved indichloromethane (0.5 mL), and TFA (0.5 mL) was added and the mixture wasstirred overnight. The reaction mixture was concentrated, loaded ontosilica gel and eluted with a gradient of 1% to 4%methanol/dichloromethane to provide the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ: ppm 12.84 (s, 1H), 8.07-7.99 (m, 1H), 7.79 (d,1H), 7.61 (d, 1H), 7.53-7.40 (m, 3H), 7.40-7.31 (m, 2H), 7.26 (s, 1H),6.95 (d, 1H), 4.95 (s, 2H), 3.96 (s, 1H), 3.93-3.82 (m, 4H), 3.01 (t,2H), 2.14 (s, 3H), 2.08 (s, 2H), 1.86-1.65 (m, 4H), 1.56 (m, 6H).

Example 606-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-cyano-3-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfonyl)phenyl]pyridine-2-carboxylicacid Example 60A2-bromo-6-(tricyclo[3.3.1.1^(3,7)]dec-1-ylthio)benzonitrile

To a solution of adamantanethiol (1.01 g) in N,N-dimethylacetamide (20mL) at room temperature was added NaH (0.24 g, 60% in mineral oil) andthe reaction was stirred for 10 minutes. 2-Fluoro-6-bromobenzonitrile (1g) was added and the mixture was heated to 80° C. for 1 hour. Thereaction mixture was cooled and diluted with ether (400 mL), and themixture was washed three times with 1M NaOH solution and once withbrine, then dried over sodium sulfate, filtered and concentrated toyield the crude product which was taken on to the next step withoutpurification.

Example 60B2-bromo-6-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfonyl)benzonitrile

A mixture of EXAMPLE 60A (1.73 g) and m-chloroperoxybenzoic acid (2.46g) in 1,2-dichloroethane (50 mL) was stirred overnight. The reaction wasdiluted with ether (300 mL), washed twice with Na₂CO₃ solution, andbrine, then dried over sodium sulfate, filtered and concentrated. Theresidue was chromatographed on silica gel using 2-50% ethyl acetate inhexanes to give the desired product.

Example 60C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-cyano-3-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfonyl)phenyl)picolinate

The title compound was prepared by substituting EXAMPLE 60B for EXAMPLE19A and EXAMPLE 4B for EXAMPLE 3D in EXAMPLE 19B.

Example 60D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-cyano-3-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfonyl)phenyl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 60C for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.65 (brs, 1H), 8.03 (d, 1H), 7.94 (d, 2H), 7.77 (m, 2H), 7.70 (d, 1H), 7.62 (m,1H), 7.44 (m, 2H), 7.30 (m, 2H), 7.12 (d, 1H), 5.06 (s, 2H), 4.02 (t,2H), 3.05 (m, 2H), 2.10 (m, 3H), 1.88 (s, 6H), 1.61 (m, 6H).

Example 616-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-[cyclooctyl(methyl)amino]-3′-methyl-3,4′-bipyridine-2-carboxylicacid Example 61A N-cyclooctyl-4-iodo-3-methylpyridin-2-amine

2-Fluoro-4-iodo-3-methylpyridine (700 mg) in cyclooctanamine (3.8 g) washeated at 130° C. overnight, cooled and diluted with dichloromethane.The resulting mixture was loaded onto a silica gel cartridge, elutingwith 0-100% dichloromethane in hexanes to provide the title compound.

Example 61B N-cyclooctyl-4-iodo-N,3-dimethylpyridin-2-amine

EXAMPLE 61A (150 mg), Cs₂CO₃ (142 mg) and CH₃I (0.027 mL) inN,N-dimethylacetamide (2 mL) was stirred at 38° C. overnight. More CH₃I(0.5 mL) and sodium hydride (52.3 mg, 60% in mineral oil) were added.The resulting mixture was stirred at 39° C. for 2 days, quenched withwater and diluted with ethyl acetate. The organic layer was washed withbrine and concentrated. The residue was purified by Prep HPLC usingGilson system eluting with 20-80% acetonitrile in 0.1% TFA/water toprovide the title compound.

Example 61C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2′-(cyclooctyl(methyl)amino)-3′-methyl-3,4′-bipyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 61B for EXAMPLE20A in EXAMPLE 20B.

Example 61D6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2′-(cyclooctyl(methyl)amino)-3′-methyl-3,4′-bipyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 61C for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.88 (s,2H), 8.01-8.07 (m, 2H), 7.79 (d, 1H), 7.63 (d, 1H), 7.59 (d, 1H),7.43-7.50 (m, 2H), 7.32-7.41 (m, 2H), 7.07 (d, 1H), 6.88 (s, 1H), 5.03(s, 2H), 3.96 (t, 2H), 3.04 (t, 2H), 2.82 (s, 3H), 2.02 (s, 3H),1.36-1.87 (m, 15H).

Example 626-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 62A 1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 10A for1-adamantanemethanol and pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 62B5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazole

To a solution of EXAMPLE 62A (0.192 g, 0.888 mmol) in tetrahydrofuran (1mL)/toluene (1 mL) was added n-butyllithium (1.6 M, 0.721 mL) at 0° C.The reaction mixture was stirred for 60 minutes. Then CH₃I (0.166 mL)was added and stirring continued for 3 hours at 0° C. The reactionmixture was quenched with water, extracted with diethyl ether, driedover Na₂SO₄, filtered, and concentrated.

Example 62C4-bromo-5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 62B for EXAMPLE3B in EXAMPLE 3C.

Example 62D tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 62C for EXAMPLE4A in EXAMPLE 4C.

Example 62E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 62D for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.53-7.40 (m, 3H),7.40-7.31 (m, 2H), 7.26 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 4.13 (d,2H), 3.91-3.85 (m, 2H), 3.02 (t, 2H), 2.18 (t, 1H), 2.13 (s, 3H), 2.00(d, 2H), 1.90-1.73 (m, 4H), 1.74-1.59 (m, 6H), 1.53 (d, 2H).

Example 636-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3-[2-(2-methoxyethoxy)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 63A1-({3-[2-(2-methoxyethoxy)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 26A for EXAMPLE7A and 2-(2-methoxyethoxy)ethanol for methanol in EXAMPLE 7B.

Example 63B1-({3-[2-(2-methoxyethoxy)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 63A for EXAMPLE3A in EXAMPLE 3B.

Example 63C4-bromo-1-({3-[2-(2-methoxyethoxy)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 63B for EXAMPLE3B in EXAMPLE 3C, with the modification that the title compound waspurified by RP-HPLC on a Gilson system, eluting with a gradient of 20%to 100% acetonitrile in water containing 0.1% v/v trifluoroacetic acid.

Example 63D tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-[1-({3-[2-(2-methoxyethoxy)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]picolinate

The title compound was prepared by substituting EXAMPLE 63C for EXAMPLE4A in EXAMPLE 4C.

Example 63E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3-[2-(2-methoxyethoxy)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 63D for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84(bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.48 (m, 3H), 7.36(m, 2H), 7.27 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.78(s, 2H), 3.48 (m, 2H), 3.44 (s, 3H), 3.22 (s, 3H), 3.02 (t, 2H), 2.10(m, 5H), 1.54 (m, 12H).

Example 646-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[(tricyclo[3.3.1.1^(3,7)]dec-2-yl]carbamoyl}phenyl)pyridine-2-carboxylicacid Example 64A3-bromo-N,2-dimethyl-N-(tricyclo[3.3.1.1^(3,7)]dec-2-yl)benzamide

The title compound was prepared by substitutingN-adamantan-2-yl-N-methyl-amine for 1-adamantanamine and3-bromo-2-methylbenzolyl chloride for 1-adamantanecarbonyl chloride inEXAMPLE 50A.

Example 64B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-2-yl]carbamoyl}phenyl)pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 64A for EXAMPLE20A in EXAMPLE 20B.

Example 64C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-2-yl]carbamoyl}phenyl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 64B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 8.03 (d,1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.50-7.32 (m, 6H), 7.20 (t, 1H),7.08-6.95 (m, 2H), 4.99 (bs, 2H), 3.92 (t, 2H), 3.03 (t, 2H), 2.94 (bs,3H), 2.22 (bs, 3H), 2.05-1.60 (m, 15H).

Example 656-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[2-(methylsulfonyl)ethoxy]cyclooctyl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 65A 1-((5-methyl-1H-pyrazol-1-yl)methyl)cyclooctanol

To a cold (−78° C.) solution of n-butyllithium (10 mL, 2.5M) intetrahydrofuran (20 mL) was added 1,5-dimethyl-1H-pyrazole (2.0 g) intetrahydrofuran (10 mL) dropwise via syringe. After 1 hour,cyclooctanone (2.63 g) in tetrahydrofuran (5 mL) was added dropwise andthe reaction mixture was allowed to warm to room temperature. Themixture was quenched by the addition of saturated ammonium chloridesolution and ethyl acetate. The layers were separated and the aqueouslayer was extracted twice with additional ethyl acetate. The combinedorganics were dried over Na₂SO₄, filtered, and concentrated to providethe title compound.

Example 65B5-methyl-1-((1-(2-(methylsulfonyl)ethoxy)cyclooctyl)methyl)-1H-pyrazole

Sodium hydride (60% dispersion in mineral oil, 200 mg) was added to astirred solution of EXAMPLE 65A (667 mg) in tetrahydrofuran (10 mL) andthe mixture was stirred at room temperature for 30 minutes before theaddition of methyl vinyl sulfone (1.27 g). The mixture was stirred atroom temperature for 3 hours. Aqueous NH₄Cl was added to quench thereaction and the mixture was extracted with ethyl acetate (three times)and the combined organic layers were washed with water and brine, driedover Na₂SO₄, and filtered. The filtrate was concentrated to provide thecrude product.

Example 65C4-iodo-5-methyl-1-((1-(2-(methylsulfonyl)ethoxy)cyclooctyl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 65B for EXAMPLE16D in EXAMPLE 16E.

Example 65D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[2-(methylsulfonyl)ethoxy]cyclooctyl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 65C for EXAMPLE4A in EXAMPLE 4B, then substituting that product for EXAMPLE 2B inEXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s, 1H),8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.42 (m, 6H), 7.31 (s, 1H),6.95 (d, 1H), 4.95 (s, 2H), 4.07 (s, 3H), 3.89 (t, 2H), 3.74 (t, 2H),3.26 (t, 2H), 3.02 (t, 2H), 2.90 (s, 3H), 2.15 (m, 3H), 1.58 (m, 14H).

Example 666-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-1,2,3-triazol-4-yl]pyridine-2-carboxylicacid Example 66A 1-(azidomethyl)-2-oxatricyclo[3.3.1.1^(3,7)]decane

The title compound was prepared by substituting1-(2-oxatricyclo[3.3.1.1^(3,7)]decyl)-methanol for 1-adamantanemethanolin EXAMPLE 57A.

Example 66B1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-5-methyl-4-(tributylstannyl)-1H-1,2,3-triazole

The title compound was prepared by substituting EXAMPLE 66A for EXAMPLE57A in EXAMPLE 57B.

Example 66C tert-butyl-3-bromo-6-fluoropicolinate

The title compound was prepared by substituting3-bromo-6-fluoropicolinic acid for 3-bromo-6-chloropicolinic acid inEXAMPLE 1D.

Example 66D tert-butyl3-(1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-5-methyl-1H-1,2,3-triazol-4-yl)-6-fluoropicolinate

The title compound was prepared by substituting EXAMPLE 66B for EXAMPLE57B and EXAMPLE 66C for EXAMPLE 57D in EXAMPLE 57E.

Example 66E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-5-methyl-1H-1,2,3-triazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 66D for EXAMPLE57E in EXAMPLE 57F.

Example 66F6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-5-methyl-1H-1,2,3-triazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 66E for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 12.72 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.59-7.67 (m, 2H),7.41-7.51 (m, 2H), 7.32-7.40 (m, 2H), 7.00 (d, 1H), 4.99 (s, 2H), 4.16(s, 2H), 3.96 (s, 1H), 3.93 (t, 2H), 3.03 (t, 2H), 2.19 (s, 3H), 2.10(s, 2H), 1.68-1.84 (m, 4H), 1.51-1.66 (m, 6H).

Example 673-[5-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid Example 67A2-(5-bromo-6-(tert-butoxycarbonyl)pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylicacid

A solution of methyl 1,2,3,4-tetrahydroisoquinoline-8-carboxylate,hydrochloric acid (13.6 g), tert-butyl 3-bromo-6-chloropicolinate (17.4g) and cesium carbonate (39 g) were stirred together inN,N-dimethylacetamide (110 mL) and heated at 120° C. under nitrogenovernight. The reaction mixture was cooled, diluted with water andextracted with ethyl acetate. The organic layer was washed with brineand the combined aqueous layers were back-extracted with ethyl acetate.The combined organic layers were dried over sodium sulfate, filtered andconcentrated. Silica gel chromatography using 20-100% ethyl acetate inhexanes provided the title compound.

Example 67B tert-butyl3-bromo-6-(8-(thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinate

The title compound was prepared by substitutingthiazolo[5,4-b]pyridin-2-amine for benzo[d]thiazol-2-amine and EXAMPLE67A for2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acidin EXAMPLE 1B.

Example 67C3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 67B for EXAMPLE1E in EXAMPLE 59D. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.98(s, 1H), 12.76 (s, 1H), 8.52 (dd, 1H), 8.16 (d, 1H), 7.62 (d, 1H),7.57-7.42 (m, 3H), 7.37 (t, 1H), 7.26 (s, 1H), 6.96 (d, 1H), 4.95 (s,2H), 3.96 (s, 1H), 3.92-3.82 (m, 4H), 3.02 (t, 2H), 2.14 (s, 3H), 2.08(s, 2H), 1.73 (m, 4H), 1.56 (m, 6H).

Example 686-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl)amino]phenyl}pyridine-2-carboxylicacid Example 68AN-(3-bromo-2-methylphenyl)-N-methyl-2-oxatricyclo[3.3.1.1^(3,7)]decyl-1-carboxamide

A mixture of oxatricyclo[3.3.1.1^(3,7)]dec-1-yl)-2-carboxylic acid (137mg) and oxalyl chloride (0.132 mL) in dichloromethane (3 mL) was stirredfor 4 days. 3-Bromo-N,2-dimethylaniline (451 mg) and triethylamine (0.2mL) were added, and the reaction mixture was stirred for 24 hours. Themixture was chromatographed on silica gel using 1-10% ethyl acetate inhexanes to give the desired product.

Example 68B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-methyl-3-(N-methyl-2-oxatricyclo[33.3.1.1^(3,7)]decyl-1-carboxamido)phenyl)picolinate

The title compound was prepared by substituting EXAMPLE 68A for EXAMPLE20A in EXAMPLE 20B.

Example 68C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl)amino]phenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 68B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.65 (brs, 1H), 8.02 (d, 1H), 7.77 (d, 1H), 7.63 (d, 1H), 7.40 (m, 5H), 7.09 (m,2H), 6.96 (m, 3H), 4.99 (s, 2H), 3.91 (t, 2H), 3.48 (m, 2H), 3.00 (s,3H), 2.18 (m, 2H), 1.75-2.01 (m, 9H), 1.69 (m, 2H), 1.51 (m, 1H), 1.33(m, 2H).

Example 696-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-2-yl]sulfamoyl}phenyl)pyridine-2-carboxylicacid Example 69A3-bromo-N,2-dimethyl-N-(tricyclo[3.3.1.1^(3,7)]dec-2-yl)benzenesulfonamide

The title compound was prepared by substitutingN-methyladamant-2-ylamine for 1-adamantanamine in EXAMPLE 51A.

Example 69B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-2-yl]sulfamoyl}phenyl)pyridine-2-carboxylicacid ter-butyl ester

The title compound was prepared by substituting EXAMPLE 69A for EXAMPLE20A in EXAMPLE 20B.

Example 69C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-2-yl]sulfamoyl}phenyl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 69B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 12.63 (bs, 1H), 8.03 (d, 1H), 7.78 (m, 2H), 7.63 (d, 1H),7.49-7.34 (m, 6H), 7.31 (td, 1H), 7.03 (d, 1H), 5.01 (bs, 2H), 3.94 (t,2H), 3.04 (t, 2H), 2.92 (s, 3H), 2.26 (s, 3H), 2.17 (bs, 2H), 1.81-1.69(m, 9H), 1.63 (bs, 2H), 1.45 (d, 2H).

Example 706-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfonyl)-3,4′-bipyridine-2-carboxylicacid

To a cooled (0° C.) solution of EXAMPLE 74B (150 mg) in dichloromethane(10 mL) was added m-chloroperoxybenzoic acid (100 mg, 77%). The mixturewas stirred at 0° C. for 30 minutes. The mixture was diluted with ethylacetate (200 mL) and washed with aqueous Na₂S₂O₃, aqueous NaHCO₃, water,and brine and dried over Na₂SO₄. After filtration, the mixture wasconcentrated and the crude product was loaded on a column and elutedwith 20% ethyl acetate in dichloromethane to give the expected product.The pure ester was then dissolved in dichloromethane/TFA (1:1, 10 mL)and stirred at room temperature overnight. After filtration, the mixturewas concentrated and the residue was dissolved in dichloromethane andloaded on a column and eluted with 5% methanol in dichloromethane toprovide the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm12.86 (s, 1H), 8.56 (d, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H),7.57 (d, 1H), 7.40 (m, 6H), 7.09 (d, 1H), 5.03 (s, 3H), 3.96 (t, 2H),3.04 (t, 2H), 2.34 (s, 3H), 2.07 (m, 4H), 1.97 (m, 6H), 1.60 (m, 6H).

Example 716-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-2-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]pyridine-2-carboxylicacid Example 71A5-methyl-1-(2-oxa-tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrole-2-carbonitrile

The title compound was prepared by substituting1-hydroxymethyl-2-oxadamantane for 1-adamantanemethanol and2-cyano-5-methylpyrrole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 71B4-bromo-5-methyl-1-(2-oxa-tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrole-2-carbonitrile

The title compound was prepared by substituting EXAMPLE 71A for EXAMPLE3B in EXAMPLE 3C.

Example 71C methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-bromopicolinate

The title compound was prepared by substituting methyl3-bromo-6-fluoropicolinate for EXAMPLE 1D in EXAMPLE 1E.

Example 71D methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate

To a solution of EXAMPLE 71C (500 mg),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (46.8 mg) and triethylamine (0.399 mL) in acetonitrile(7 mL) and tetrahydrofuran (3.5 mL) was added4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.416 mL). The mixture washeated at 100° C. in a Biotage Initiator microwave reactor for 30minutes, cooled, diluted with ethyl acetate, and washed with brine. Theorganic layer was concentrated. The residue was purified by flashchromatography, eluting with 0-17% ethyl acetate in dichloromethane toprovide the title compound.

Example 71E6-[8-(Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[5-cyano-2-methyl-1-(2-oxa-tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]-pyridine-2-carboxylicacid methyl ester

The title compound was prepared by substituting EXAMPLE 71D for EXAMPLE4B and EXAMPLE 71B for EXAMPLE 20A in EXAMPLE 20B.

Example 71F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-2-methyl-1-(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 71E for EXAMPLE72C in EXAMPLE 72D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(s, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42-7.50 (m, 3H),7.33-7.39 (m, 2H), 6.95 (d, 1H), 6.78 (s, 1H), 4.96 (s, 2H), 3.97 (s,1H), 3.85-3.92 (m, 4H), 3.01 (t, 2H), 2.12 (s, 5H), 1.69-1.85 (m, 4H),1.52-1.65 (m, 6H).

Example 726-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-cyano-2-methyl-1-[(3-methyl-2-oxatricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrrol-3-yl}pyridine-2-carboxylicacid Example 72A5-methyl-1-(3-methyl-2-oxa-tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrole-2-carbonitrile

The title compound was prepared by substituting1-hydroxymethyl-3-methyl-2-oxadamantane for 1-adamantanemethanol and2-cyano-5-methylpyrrole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 72B4-bromo-5-methyl-1-(3-methyl-2-oxa-tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrole-2-carbonitrile

The title compound was prepared by substituting EXAMPLE 72A for EXAMPLE3B in EXAMPLE 3C.

Example 72C6-[8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[5-cyano-2-methyl-1-(3-methyl-2-oxa-tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]-pyridine-2-carboxylicacid methyl ester

The title compound was prepared by substituting EXAMPLE 71D for EXAMPLE4B and EXAMPLE 72B for EXAMPLE 20A in EXAMPLE 20B.

Example 72D6-[8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3-[5-cyano-2-methyl-1-(3-methyl-2-oxa-tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrrol-3-yl]pyridine-2-carboxylicacid

EXAMPLE 72C (80 mg) in tetrahydrofuran (8 mL) and methanol (3 mL) wastreated with 2N aqueous NaOH (3 mL) overnight. The reaction mixture wasconcentrated and the residue was purified by reverse phasechromatography using a Gilson system, eluting with 40%-100% acetonitrilein 0.1% TFA water solution to provide the title compound. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d,1H), 7.62 (d, 1H), 7.42-7.49 (m, 3H), 7.36 (q, 2H), 6.95 (d, 1H), 6.77(s, 1H), 4.96 (s, 2H), 3.87-3.91 (m, 4H), 3.01 (t, 2H), 2.11-2.17 (m,5H), 1.63-1.74 (m, 2H), 1.56 (d, 2H), 1.38-1.51 (m, 6H), 1.00 (s, 3H).

Example 736-[8-(imidazo[1,2-a]pyrazin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 73A Imidazo[1,2-a]pyrazin-2-amine

2,2,2-Trifluoro-N-(imidazo[1,2-a]pyrazin-2-yl)acetamide (prepared asdescribed in WO2004/058266A1, 520 mg) was dissolved in 7N NH₃ inmethanol (4.0 mL), and heated at 68° C. in a sealed tube for 6 hours.The reaction mixture was then cooled and concentrated to provide thetitle compound.

Example 73B6-[8-(imidazo[1,2-a]pyrazin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 73A forthiazolo[4,5-b]pyridine-2-amine in EXAMPLE 30D, with the exception that1/1 CH₂Cl₂/ethyl acetate, then 100% ethyl acetate were used for theeluents.

Example 73C6-[8-(imidazo[1,2-a]pyrazin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

EXAMPLE 73B (85 mg) was dissolved in dichloromethane (1.5 mL) andtrifluoroacetic acid (1.5 mL). After stirring at room temperatureovernight the reaction mixture was concentrated, then dissolved inCH₂Cl₂ (10 mL) and washed with water (5×15 mL). The organic layer wasdried over Na₂SO₄. After filtration and concentration, the residue wastriturated with CH₃CN (10 mL) to provide the title compound. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ ppm 11.49 (br s, 1H), 8.93 (s, 1H), 8.64(dd, 1H), 8.55 (s, 1H), 7.92 (d, 1H), 7.51 (m, 2H), 7.37 (d, 1H), 7.33(t, 1H), 7.27 (s, 1H), 6.90 (d, 1H), 4.92 (s, 2H), 3.88 (t, 2H), 3.70(s, 2H), 3.02 (t, 2H), 2.10 (s, 3H), 1.92 (br s, 3H), 1.64 (br d, 3H),1.54 (br m, 9H).

Example 746-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl)-3,4′-bipyridine-2-carboxylicacid Example 74A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2′-fluoro-3′-methyl-3,4′-bipyridine-2-carboxylate

The title compound was prepared by substituting2-fluoro-4-iodo-3-methylpyridine for EXAMPLE 20A in EXAMPLE 20B.

Example 74B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-an-3-ylthio)-3′-methyl-3,4′-bipyridine-2-carboxylate

To a solution of EXAMPLE 74A (130 mg) in N,N-dimethylacetamide (4 mL)was added 1-adamantanethiol (111 mg) and Cs₂CO₃ (215 mg). The mixturewas stirred at 120° C. under microwave conditions (Biotage) for 2 hours.The mixture was diluted with ethyl acetate (200 mL) and washed withwater and brine and dried over Na₂SO₄. After filtration and evaporationof the solvent, the crude material was loaded on a column and elutedwith 20% ethyl acetate in dichloromethane to provide the title compound.

Example 74C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl)-3,4′-bipyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 74B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.25 (d, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.43 (m,5H), 7.03 (d, 1H), 6.83 (d, 1H), 5.00 (s, 2H), 3.93 (t, 2H), 3.03 (t,2H), 2.26 (m, 5H), 2.01 (m, 3H), 1.95 (s, 3H), 1.71 (m, 6H).

Example 752-{6-[(methylsulfonyl)carbamoyl]-5-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-([1,3]thiazolo[5,4-b]pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

The title compound was prepared by substituting EXAMPLE 24B for EXAMPLE3F in EXAMPLE 17, with the exception that chromatography on silica gelusing 70/30/1 hexanes/ethyl acetate/acetic acid was used for thepurification. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 11.82 (br s,1H), 8.52 (dd, 1H), 8.15 (dd, 1H), 7.63 (d, 1H), 7.52 (m, 2H), 7.38 (t,1H), 7.33 (t, 1H), 7.27 (s, 1H), 7.02 (d, 1H), 4.97 (s, 2H), 3.93 (t,2H), 3.70 (s, 2H), 3.12 (s, 3H), 3.03 (t, 2H), 2.11 (s, 3H), 1.92 (br s,3H), 1.64 (br d, 3H), 1.54 (br m, 9H).

Example 766-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylamino)-3,4′-bipyridine-2-carboxylicacid Example 76A4-iodo-3-methyl-N-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)pyridin-2-amine

The title compound was prepared by substituting adamantine-1-amine forcyclooctanamine in EXAMPLE 61A.

Example 76B2′-(adamantan-1-ylamino)-6-[8-(benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3′-methyl-[3,4′]bipyridinyl-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 76A for EXAMPLE20A in EXAMPLE 20B.

Example 76C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylamino)-3,4′-bipyridine-2-carboxylicacid

EXAMPLE 76B (100 mg) in tetrahydrofuran (8 mL) and methanol (5 mL) wastreated with 2 N aqueous NaOH (5 mL) at 50° C. for 5 days, cooled, andacidified to pH 1. The mixture was concentrated and the residue waspurified reverse phase chromatography using a Gilson system, elutingwith 30%-70% acetonitrile in 0.1 TFA/water to provide the titlecompound. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (s, 2H),8.03 (d, 1H), 7.83 (d, 1H), 7.79 (d, 1H), 7.64 (d, 1H), 7.44-7.52 (m,3H), 7.33-7.40 (m, 2H), 7.07 (d, 1H), 6.63 (s, 1H), 5.03 (s, 2H), 3.95(s, 2H), 3.03 (t, 2H), 1.93 (s, 3H), 1.71-1.81 (m, 3H), 1.63-1.70 (m,3H).

Example 776-[8-(imidazo[1,2-b]pyridazin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 77A6-[8-(imidazo[1,2-b]pyridazin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substitutingimidazo[1,2-b]pyridazin-2-amine for thiazolo[4,5-b]pyridine-2-amine inEXAMPLE 30D, with the exception that 45-60% ethyl acetate in CHCl₃ wasused for the eluent.

Example 77B6-[8-(imidazo[1,2-b]pyridazin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 77A for EXAMPLEIF in EXAMPLE 1G. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 11.41 (brs, 1H), 8.50 (dd, 1H), 8.49 (s, 1H), 8.02 (d, 1H), 7.49 (m, 2H), 7.37(d, 1H), 7.33 (t, 1H), 7.27 (s, 1H), 7.25 (dd, 1H), 6.92 (d, 1H), 4.92(s, 2H), 3.88 (t, 2H), 3.71 (s, 2H), 3.00 (t, 2H), 2.10 (s, 3H), 1.93(br s, 3H), 1.64 (br d, 3H), 1.54 (br m, 9H).

Example 783-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid Example 78A3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substitutingthiazolo[5,4-c]pyridin-2-amine for thiazolo[4,5-b]pyridine-2-amine inEXAMPLE 30D.

Example 78B3-[5-methyl-1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1H-pyrazol-4-yl]-6-[8-([1,3]thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 78A for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm13.77-13.39 (s, 1H), 12.75 (s, 1H), 9.46 (s, 1H), 8.70 (d, 1H), 8.03 (d,1H), 7.71-7.64 (m, 1H), 7.55-7.45 (m, 2H), 7.40 (t, 1H), 7.26 (s, 1H),6.97 (d, 1H), 4.98 (s, 2H), 3.89 (m, 2H), 3.70 (s, 2H), 3.02 (t, 2H),2.10 (s, 3H), 1.92 (s, 3H), 1.60 (m, 12H).

Example 796-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(5-methoxyspiro[2.5]oct-5-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 79A Spiro[2.5]octan-5-one

3-Ethoxycyclohex-2-enone (25 g) was dissolved in diethyl ether (500 mL),and tetraisopropoxytitanium (55 mL) was added, followed by the additionof ethyl magnesium bromide (3.0 Min diethyl ether, 180 mL) over 30minutes. The reaction was stirred at room temperature for another twohours, and quenched by the careful addition of water (250 mL). Themixture was filtered through diatomaceous earth, and rinsed with diethylether. The filtrate was transferred to a separatory funnel, the aqueouslayer was drawn off, and p-toluenesulfonic acid monohydrate (2 g) wasadded to the organic layer, which was stirred at room temperature fortwo days. The reaction mixture was washed with saturated aqueous NaHCO₃and brine, then dried over Na₂SO₄. The mixture was filtered, andconcentrated and chromatography on silica gel using 93/7 hexanes/ethylacetate provided the title compound.

Example 79B 5-((5-methyl-1H-pyrazol-1-yl)methyl)spiro[2.5]octan-5-ol

Tetrahydrofuran (50 mL) was cooled to −76° C., n-butyllithium (2.5M intetrahydrofuran, 7.0 mL) was added, and the solution was cooled back to−76° C. 1,5-Dimethyl-1H-pyrazole (1.5 g) was added dropwise, and thereaction was stirred for 75 minutes. EXAMPLE 79A (2.15 g) was addeddropwise, and the mixture was stirred for another 15-20 minutes. Thereaction mixture was warmed to room temperature, and partitioned betweensaturated NH₄Cl and ethyl acetate. The organic layer was washed withbrine, dried over Na₂SO₄, filtered, and concentrated. Chromatography onsilica gel using 4/1 hexanes/ethyl acetate provided the title compound.

Example 79C1-((5-methoxyspiro[2.5]octan-5-yl)methyl)-5-methyl-1H-pyrazole

EXAMPLE 79B (1 g) was dissolved in N,N-dimethylformamide (15 mL), theniodomethane (0.85 mL) and 95% sodium hydride (340 mg) were added. Thereaction was stirred at room temperature for 2.5 hours, then dilutedwith water and extracted with ethyl acetate. The organic layer waswashed with brine and dried over sodium sulfate. Filtration andconcentration provided the title compound.

Example 79D4-bromo-1-((5-methoxyspiro[2.5]octan-5-yl)methyl)-5-methyl-1H-pyrazole

EXAMPLE 79C (1.1 g) was dissolved in N,N-dimethylformamide (12 mL), andN-bromosuccinimide (840 mg) was added. The reaction mixture was stirredat room temperature for 2.5 hours, and diluted with water and extractedwith ethyl acetate. The organic layer was washed with 20% aqueous Na₂SO₃and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated to provide the title compound.

Example 79E1-((5-methoxyspiro[2.5]octan-5-yl)methyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 79D for EXAMPLE3C in EXAMPLE 3D.

Example 79F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(5-methoxyspiro[2.5]oct-5-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 79E for EXAMPLE3D and EXAMPLE 1E for EXAMPLE 14C in EXAMPLE 14D.

Example 79G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(5-methoxyspiro[2.5]oct-5-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

EXAMPLE 79F (40 mg) was dissolved in tetrahydrofuran (0.2 mL) andmethanol (0.3 mL). To the mixture was added 1N LiOH (0.35 mL), and thereaction mixture was stirred at 60° C. overnight. After cooling to roomtemperature, the mixture was diluted with water (5 mL), 2N aqueous HCl(0.18 mL) was added, and the solution was extracted with ethyl acetateand concentrated. The residue was purified by Prep HPLC using a Gilsonsystem eluting with 20-80% acetonitrile in 0.1% water. The desiredfractions were combined and freeze-dried to provide the title compound.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (v br s, 1H), 8.04(d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.48 (m, 2H), 7.43 (d, 1H), 7.36(m, 2H), 7.28 (s, 1H), 6.95 (d, 1H), 4.96 (s, 2H), 4.19 (d, 1H), 4.09(d, 1H), 3.89 (t, 2H), 3.09 (s, 3H), 3.01 (t, 2H), 2.12 (s, 3H), 1.58(br m, 3H), 1.43 (br m, 3H), 1.20 (br m, 2H), 0.31 (br m, 2H), 0.23 (brm, 2H).

Example 806-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 80A1-[(3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 26A for EXAMPLE7A and 2-(2-(2-methoxyethoxy)ethoxy)ethanol for methanol in EXAMPLE 7B.

Example 80B1-1-{[3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 80A for EXAMPLE3A in EXAMPLE 3B.

Example 80C1-{[3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl})-4-bromo-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 80B for EXAMPLE3B in EXAMPLE 3C, with the modification that the title compound waspurified by RP-HPLC on a Gilson system, eluting with a gradient of 20%to 100% acetonitrile in water containing 0.1% v/v trifluoroacetic acid.

Example 80D tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-{[3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 80C for EXAMPLE4A in EXAMPLE 4C.

Example 80E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 80D for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84(bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.41 (m, 5H), 7.27(s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.78 (s, 1H), 3.49(m, 6H), 3.43 (m, 6H), 3.22 (s, 3H), 3.02 (t, 2H), 2.11 (m, 5H), 1.53(m, 12H).

Example 816-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(methylsulfonyl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 81A3-(1H-pyrazol-1-ylmethyl)tricyclo[3.3.1.1^(3,7)]decane-1-thiol

A solution of EXAMPLE 26A (2.0 g) and thiourea (2.0 g) in a solventmixture of acetic acid (20 mL) and 48% aqueous HBr solution (10 mL) washeated to 100° C. for 24 hours. The reaction was concentrated todryness, and the residue was dissolved in 20% v/v ethanol in water (100mL). Solid sodium hydroxide (10 g) was added, and the mixture wasstirred overnight. The solution was acidified to pH 1 with concentratedHCl solution, and diluted with ethyl acetate (100 mL). The layers wereseparated, and the aqueous layer was extracted with additional ethylacetate (2×100 mL). The combined organic layers were washed with water,dried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby silica gel chromatography, eluting with a gradient of 10-50% ethylacetate in hexane, to give the title product.

Example 81B1-{[3-(methylsulfanyl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazole

To a solution of EXAMPLE 81A (300 mg) in methanol (2 mL) was addedsodium methoxide (4 mL, 0.5 M in methanol). Iodomethane (0.5 mL) wasadded, and the reaction heated to reflux for 3 hours. The reaction wascooled to room temperature and concentrated to dryness. The residue warpurified by reverse phase HPLC, eluting with a gradient of 30% to 100%acetonitrile in water containing 0.1% v/v trifluoroacetic acid, to givethe title product.

Example 81C5-methyl-1-{[3-(methylsulfanyl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 81B for EXAMPLE3A in EXAMPLE 3B.

Example 81D4-bromo-5-methyl-1-{[3-(methylsulfonyl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazole

To a solution of EXAMPLE 81C (98 mg) in water (2 mL) was addedN-bromosuccinimide (150 mg), and the reaction mixture was heated toreflux for 3 hours. Additional N-bromosuccinimide (50 mg) was added, andthe reaction was heated to reflux for 24 hours. The reaction mixture wascooled to room temperature and diluted with methylene chloride. Thelayers were separated, and the aqueous layer was extracted withadditional methylene chloride (twice). The combined organic layers werewashed with water, dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by flash chromatography, eluting with a gradient of0-50% ethyl acetate in hexane, to provide the title compound.

Example 81E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-methyl-1-{[3-(methylsulfonyl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 81D for EXAMPLE4A in EXAMPLE 4C.

Example 81F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(methylsulfonyl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 81E for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.04 (d, 5, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.48 (m, 3H),7.36 (d, 2H), 7.30 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H),3.80 (s, 2H), 3.02 (d, 2H), 2.19 (m, 11H), 1.57 (m, 6H).

Example 826-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,5-dimethyl-7-[2-(methylamino)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 82A2-{[3,5-dimethyl-7-(1H-pyrazol-1-ylmethyl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]oxy}ethanol

To a solution of EXAMPLE 38C (4.5 g) in ethane-1,2-diol (12 mL) wasadded triethylamine (3 mL) under nitrogen. The mixture was heated to150° C. under microwave conditions (Biotage) for 45 minutes. The mixturewas poured over water (100 mL) and extracted with ethyl acetate (3×200mL). The combined organic layers were washed with water and brine, driedwith Na₂SO₄, filtered and concentrated. The residue was purified bysilica gel chromatography, eluting with 20% ethyl acetate in hexane (1L) followed by 5% methanol in methylene chloride (1 L), to give thetitle product.

Example 82B2-({3,5-dimethyl-7-[(5-methyl-1H-pyrazol-1-yl)methyl]tricyclo[3.3.1.1^(3,7)]dec-1-yl}oxy)ethanol

To a cold (−78° C.) solution of the EXAMPLE 82A (3.69 g) intetrahydrofuran (50 mL) was added n-BuLi (20 mL, 2.5 M in hexane) undernitrogen. The mixture was stirred at −78° C. for 1.5 hours. Iodomethane(10 mL) was added by syringe, and the mixture was stirred for anadditional 3 hours. The reaction mixture was then quenched by theaddition of aqueous ammonium chloride solution and extracted with ethylacetate (2×200 mL). The combined organic layers were washed with water(60 mL) and brine (60 mL), dried with Na₂SO₄, filtered and concentrated.The residue was purified by silica gel column chromatography, elutingwith 5% methanol in methylene chloride, to give the title compound.

Example 82C1-({3,5-dimethyl-7-[2-(hydroxy)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-4-iodo-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 82B for EXAMPLE16D in EXAMPLE 16E.

Example 82D2-({3-[(4-iodo-5-methyl-1H-pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl}oxy)ethylmethanesulfonate

To a cold (0° C.) solution of EXAMPLE 82C (2.1 g) in methylene chloride(30 mL) was added triethylamine (1.42 g) followed by methanesulfonylchloride (0.542 g). The mixture was stirred at room temperature for 1.5hours and then was diluted with ethyl acetate (300 mL). The layers wereseparated, and the organic layer was washed with water (60 mL) and brine(60 mL), dried with Na₂SO₄, filtered and concentrated to give the titlecompound, which was used in the next step without further purification.

Example 82E1-({3,5-dimethyl-7-[2-(methylamino)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-4-iodo-5-methyl-1H-pyrazole

A solution of the EXAMPLE 82D (2.5 g) in 2 M methylamine in methanol (15mL) was heated to 100° C. for 20 minutes under microwave conditions(Biotage). The reaction mixture was concentrated, and the residue wasdiluted with ethyl acetate (400 mL). The organic layer was washed withsaturated aqueous NaHCO₃ solution (60 mL), water (60 mL) and brine (60mL). The organic layer was dried with Na₂SO₄, filtered and concentratedto give the title compound, which was used in the next reaction withoutfurther purification.

Example 82F tert-butyl[2-({3-[(4-iodo-5-methyl-1H-pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl}oxy)ethyl]methylcarbamate

To a solution of EXAMPLE 82E (2.2 g) in tetrahydrofuran (30 mL) wasadded Boc₂O (1.26 g) and a catalytic amount of 4-dimethylaminopyridine.The mixture was stirred at room temperature for 1.5 hours and dilutedwith ethyl acetate (300 mL). The solution was washed with saturatedaqueous NaHCO₃, water (60 mL) and brine (60 mL). The organic layer wasdried with Na₂SO₄, filtered and concentrated. The residue was purifiedby silica gel chromatography, eluting with 20% ethyl acetate inmethylene chloride, to give the title compound.

Example 82G tert-butyl{2-[(3,5-dimethyl-7-{[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}tricyclo[3.3.1.1^(3,7)]dec-1-yl)oxy]ethyl}methylcarbamate

The title compound was prepared by substituting EXAMPLE 82F for EXAMPLE59B in EXAMPLE 59C.

Example 82H tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3-{2-[(tert-butoxycarbonyl)(methyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl})pyridine-2-carboxylate

A solution of a 3:1 ratio of dioxane and water (40 mL) was degassed withnitrogen for 45 minutes. This solution was added to EXAMPLE 1E (01.5 g),EXAMPLE 82G (1.48 g), potassium phosphate (02.82 g),tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.121 g) and1,3,5,7-tetramethyl-6-tetradecane-2,4,8-trioxa-6-phosphaadamantane(0.194 g). The mixture was degassed and heated to 90° C. under nitrogenovernight. The reaction mixture was cooled, diluted with ethyl acetate(100 mL), washed with water (three×50 mL) and brine (50 mL), dried overmagnesium sulfate, filtered and concentrated. The residue was purifiedby silica gel chromatography, eluting with a gradient of 20% to 40%ethyl acetate in methylene chloride, to give the title compound.

Example 82I6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,5-dimethyl-7-[2-(methylamino)ethoxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 82H for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.21 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.43 (m,4H), 6.96 (d, 1H), 4.96 (s, 2H), 3.89 (m, 6H), 3.54 (m, 2H), 3.01 (t,4H), 2.55 (t, 3H), 2.10 (s, 3H), 1.42 (s, 2H), 1.31 (m, 4H), 1.08 (m,6H), 0.87 (s, 6H).

Example 836-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[3-(2-{2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 83A2-[2-(2-{[3-(1H-pyrazol-1-ylmethyl)tricyclo[3.3.1.1^(3,7)]dec-1-yl]oxy}ethoxy)ethoxy]ethanol

The title compound was prepared by substituting EXAMPLE 26A for EXAMPLE7A and 2,2′-(ethane-1,2-diylbis(oxy))diethanol for methanol in EXAMPLE7B., with the modification that the title compound was purified byRP-HPLC on a Gilson system, eluting with a gradient of 20% to 100%acetonitrile in water containing 0.1% v/v trifluoroacetic acid.

Example 83B2-{2-[2-({3-[(5-methyl-1H-pyrazol-1-yl)methyl]tricyclo[3.3.1.1^(3,7)]dec-1-yl}oxy)ethoxy]ethoxy}ethanol

To a cold (−78° C.) solution of EXAMPLE 83A (1.0 g) in tetrahydrofuran(10 mL) was added n-BuLi (5 mL, 2.5 M in hexane). The reaction mixturewas stirred for 90 minutes, and iodomethane (1 mL) was added. Thereaction mixture was stirred at −78° C. for 90 minutes and quenched bythe addition of 1 drop of trifluoroacetic acid. The reaction mixture waswarmed to room temperature and concentrated to dryness. The residue wasused in the subsequent step without further purification.

Example 83C2-{2-[2-({3-[(4-iodo-5-methyl-1H-pyrazol-1-yl)methyl]tricyclo[3.3.1.1^(3,7)]dec-1-yl}oxy)ethoxy]ethoxy}ethanol

To an ambient solution of EXAMPLE 83B (0.54 g) in N,N-dimethylformamide(5 mL) was added N-iodosuccinimide (0.35 g). The reaction mixture wasstirred for 2 hours, and the crude reaction solution was purified byRP-HPLC on a Gilson system, eluting with a gradient of 20% to 100%acetonitrile in water containing 0.1% v/v trifluoroacetic acid, to givethe title compound.

Example 83D2-{2-[2-({3-[(4-iodo-5-methyl-1H-pyrazol-1-yl)methyl]tricyclo[3.3.1.1^(3,7)]dec-1-yl}oxy)ethoxy]ethoxy}-N-methylethanamine

To a cold (0° C.) solution of EXAMPLE 83C (0.445 g) and triethylamine(0.5 mL) in tetrahydrofuran (10 mL) was added methanesulfonyl chloride(0.07 mL). The mixture was stirred for 3 hours and transferred to a20-mL microwave reaction vessel. Methanamine (4 mL, 2 M in methanol) wasadded, and the mixture was heated to 100° C. for 20 minutes undermicrowave (Biotage) conditions. The reaction mixture was concentrated todryness, and the residue was purified by reverse-phase chromatography(Analogix system, C18 SF40-300 g column), eluting with a gradient of40-100% acetonitrile in water containing 0.1% v/v trifluoroacetic acid,to give the title product.

Example 83E tert-butyl(2-{2-[2-({3-[(4-iodo-5-methyl-1H-pyrazol-1-yl)methyl]tricyclo[3.3.1.1^(3,7)]dec-1-yl})oxy)ethoxy]ethoxy})ethyl)methylcarbamate

The title compound was prepared by substituting EXAMPLE 83D for EXAMPLE82E in EXAMPLE 82F.

Example 83F tert-butylmethyl[2-(2-{2-[(3-{[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}tricyclo[3.3.1.1^(3,7)]dec-1-yl)oxy]ethoxy}ethoxy)ethyl]carbamate

The title compound was prepared by substituting EXAMPLE 83E for EXAMPLE59B in EXAMPLE 59C.

Example 83G

tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({3-[(2,2,5-trimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)oxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 83F for EXAMPLE4A in EXAMPLE 4C.

Example 83H6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[(3-(2-{2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 83G for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(bs, 1H), 8.37 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.47(m, 2H), 7.36 (m, 2H), 7.28 (s, 1H), 6.95 (d, 1H), 4.96 (s, 1H), 3.88(dd, 2H), 3.56 (m, 4H), 3.46 (m, 3H), 3.06 (m, 4H), 2.55 (m, 3H), 2.09(m, 5H), 1.48 (m, 12H).

Example 846-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({8-[(benzyloxy)carbonyl]-8-azabicyclo[3.2.1]oct-3-yl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 84A Benzyl8-azaspiro[bicyclo[3.2.1]octane-3,2′-oxirane]-8-carboxylate

To a 500-mL, three-necked, round-bottomed flask equipped with a magneticstirring bar, a thermometer, and a condenser was charged tetrahydrofuran(163 mL), potassium tert-butoxide (6.6 g, 95% pure) andtrimethylsulfoxonium iodide (13.0 g). The mixture was heated to refluxand stirred for 3 hours. A solution of benzyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10.0 g) intetrahydrofuran (37 mL) was added in one portion. The reaction mixturewas refluxed for another 2 hours. The mixture was cooled to roomtemperature and diluted with toluene (100 mL) and water. The water layerwas separated and extracted with toluene (2×50 mL). The combined organiclayers were washed with water (3×40 mL) and concentrated under vacuum toprovide the title compound.

Example 84B Benzyl 3-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate

To a cold (0° C.) solution of EXAMPLE 84A (3.5 g) in tetrahydrofuran (40mL) was added boron trifluoride diethyl ether complex (0.82 mL). Themixture was stirred at 3-5° C. for 3 hours. Aqueous saturated NaHCO₃ wasadded, followed by ethyl acetate (200 mL). The organic layer wasseparated, washed with water (twice) and concentrated to dryness.Toluene was added and the mixture was concentrated under vacuum toprovide the title compound.

Example 84C Benzyl3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

To a solution of EXAMPLE 84B (3.4 g) in tetrahydrofuran (40 mL) wasadded NaBH₄ (0.5 g). The mixture was stirred overnight. The solvent wasevaporated and the residue was added to ethyl acetate (300 mL) and water(50 mL). The organic layer was washed with water and brine, dried overNa₂SO₄, and filtered. Evaporation of the solvent gave the crude titlecompound.

Example 84D Benzyl3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

The title compound was prepared by substituting EXAMPLE 84C for1-adamantanemethanol and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 2A.

Example 84E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({8-[(benzyloxy)carbonyl]-8-azabicyclo[3.2.1]oct-3-yl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 84D for EXAMPLE1A in EXAMPLE 1F, and then substituting that product for EXAMPLE 2B inEXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s, 1H),8.04 (d, 1H), 7.49 (m, 16H), 6.94 (d, 1H), 5.06 (m, 2H), 4.94 (s, 2H),3.89 (m, 3H), 3.00 (m, 2H), 1.84 (m, 3H), 1.59 (m, 2H), 1.29 (m, 6H).

Example 856-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-6′-oxo-1′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1′,6′-dihydro-3,3′-bipyridine-2-carboxylicacid Example 85A1-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-5-bromopyridin-2(1H)-one

To an ambient suspension of NaH (185 mg, 4.63 mmol, 60% dispersion inmineral oil) in N,N-dimethylformamide (30 mL) was added5-bromopyridin-2(1H)-one (700 mg, 4.02 mmol). The reaction mixture wasstirred for 15 minutes, and 1-(bromomethyl)adamantane (968 mg 4.22 mmol)was added. The mixture was heated to 120° C. overnight, cooled to roomtemperature, and quenched by the addition of water and ether. The layerswere separated, and the aqueous extracted with additional ether (twice).The combined organics were washed with brine, dried over Na₂SO₄, andfiltered. Chromatography on silica gel, eluting with a gradient of 5 to30% ethyl acetate in hexanes, provided the title compound.

Example 85B tert-butyl1′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-6′-oxo-1′,6′-dihydro-[3,3′-bipyridine]-2-carboxylate

The title compound was prepared by substituting EXAMPLE 85A for EXAMPLE4A in EXAMPLE 4C.

Example 85C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-6′-oxo-1′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1′,6′-dihydro-3,3′-bipyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 85B for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.66-7.54 (m, 3H), 7.50-7.31 (m,5H), 7.01 (d, 1H), 6.39 (d, 1H), 4.98 (s, 2H), 3.90 (t, 2H), 3.66 (s,2H), 3.01 (t, 2H), 1.92 (bs, 3H), 1.68-1.46 (m, 12H).

Example 866-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyl-7-(2-{2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 86A1-{[3,5-dimethyl-7-(2-{2-[2-(hydroxy)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 38C for EXAMPLE7A and 2,2′-(ethane-1,2-diylbis(oxy))diethanol for methanol in EXAMPLE7B, with the modification that the title compound was purified byRP-HPLC on a Gilson system, eluting with a gradient of 20% to 100%acetonitrile in water containing 0.1% v/v trifluoroacetic acid.

Example 86B1-{[3,5-dimethyl-7-(2-{2-[2-(hydroxy)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 86A for EXAMPLE83A in EXAMPLE 83B.

Example 86C1-{[3,5-dimethyl-7-(2-{2-[2-(hydroxy)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl}-4-iodo-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 86B for EXAMPLE83B in EXAMPLE 83C.

Example 86D 1-{[3,5-dimethyl-7-(2-{2-[2-(methylamino)ethoxy]ethoxy})ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl})-4-iodo-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 86C for EXAMPLE83C in EXAMPLE 83D.

Example 86E tert-butyl(2-{2-[2-({3-[(4-iodo-5-methyl-1H-pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1^(3,7)]dec-1-yl}oxy)ethoxy]ethoxy})ethyl)methylcarbamate

The title compound was prepared by substituting EXAMPLE 86D for EXAMPLE82E in EXAMPLE 82F.

Example 86F tert-butyl[2-(2-{2-[(3,5-dimethyl-7-{[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}tricyclo[3.3.1.1^(3,7)]dec-1-yl)oxy]ethoxy}ethoxy)ethyl]methylcarbamate

The title compound was prepared by substituting EXAMPLE 86E for EXAMPLE59B in EXAMPLE 59C.

Example 86G tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,5-dimethyl-7-[(2,2,5-trimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)oxy]tricyclo[3.3.1.1^(3,7)]dec-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 86F for EXAMPLE4A in EXAMPLE 4C.

Example 86H6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,5-dimethyl-7-(2-{2-[2-(methylamino)ethoxy]ethoxy}ethoxy)tricyclo[3.3.1.1^(3,7)]dec-1-yl]methyl})-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 86G for EXAMPLE2B in EXAMPLE 2C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.33 (bs, 2H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.48(m, 3H), 7.36 m, 2H), 7.28 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.86 (m,4H), 3.63 (m, 2H), 3.55 (s, 4H), 3.05 (d, 4H), 2.56 (t, 2H), 2.10 (s,3H), 1.27 (m, 6H), 1.06 (m, 6H), 0.85 (s, 6H).

What is claimed is:
 1. A compound or therapeutically acceptable saltthereof, wherein the compound is selected from the group consisting of6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-4-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy]phenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-3,4′-bipyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethoxy)-3,4′-bipyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-yloxy]phenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylamino]phenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl]phenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfamoyl]phenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl]amino}phenyl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[tricyclo[3.3.1.1^(3,7)]dec-1-ylcarbamoyl]phenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl]amino}phenyl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-cyano-3-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfonyl)phenyl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbanoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-[cyclooctyl(methyl)amino]-3′-methyl-3,4′-bipyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-2-yl]carbamoyl}phenyl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(2-oxatricyclo[3.3.1.1^(3,7)]dec-1-ylcarbonyl)amino]phenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[tricyclo[3.3.1.1^(3,7)]dec-2-yl]sulfamoyl}phenyl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfonyl)-3,4′-bipyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylsulfanyl)-3,4′-bipyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylamino)-3,4′-bipyridine-2-carboxylicacid; and6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-6′-oxo-1′-(tricyclo[3.3.1.1^(3,7)]dec-1-ylmethyl)-1′,6′-dihydro-3,3′-bipyridine-2-carboxylicacid.
 2. A composition comprising an excipient and a therapeuticallyeffective amount of the compound or therapeutically acceptable salt ofclaim 1.